Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS FOR TREATING AND/OR PREVENTING DISEASES
CHARACTERIZED BY THE PRESENCE OF METAL IONS
FIELD OF THE INVENTION
This invention generally relates to the treatment and/or prevention of
diseases
characterized by the presence of metal ions, such as Alzheimer's disease and,
in
particular, to the treatment and/or prevention of such diseases using certain
compositions
comprising chelating agents and/or silicon compounds.
io DESCRIPTION OF THE RELATED ART
Many diseases can be characterized by an excess or an imbalance of metal ions
within the body, for example, within an organ or a tissue. An excess of metal
ions may,
in some cases, affect protein structure or function, or lead to or facilitate
certain diseases,
such as Alzheimer's disease, Parkinson's disease, various homeostatic
diseases, cardiac
15 arrhythmia, various central nervous system (CNS) disorders, blood plasma
imbalances,
dermatitis, Gerstmann-Staussler-Scheinker disorder, familial insomnia,
Menkes's
syndrome, lead poisoning and other heavy metal toxicities, or various prion
diseases
such as transmissible spongiform encephalopathy or Creutzfeld-Jakob disease.
Tn some
cases, an excess of metal ions may also interfere with ion channel function,
protein
2o structure or folding, or enzyme function, which can lead to disease states.
For example,
many proteins and enzymes use metal ions to stabilize their conformation at or
as a
reactive site.
Physiological removal or sequestration of metal ions may be useful in treating
such diseases. However, very few biocompatible agents able to bind ions that
can be
25 delivered to a target site are known to exist. One example of a compound
able to bind
ions within the body is ethylenediaminetetraacetic acid ("EDTA"). The half
life of
EDTA in the body, however, is relatively short. Typical doses of EDTA last for
only
about 1 hour in the body, limiting the effectiveness of this form of
treatment.
One disease that can be characterized by an excess of metal ions is
Alzheimer's
3o disease. Alzheimer's disease is a common form of senile dementia. Some
studies have
suggested that 25-50% of all people in their eighties may have Alzheimer's
disease.
Symptoms of Alzheimer's disease include memory loss, loss of language or
cognitive
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ability, declines in reasoning ability, and reduced use of speech. Behavioral
disorders
may also be present. Changes in brain physiology may also occur, for example,
enlarged
ventricles, narrow cortical gyri, or widened sulci. These changes have been
attributed to
neuronal loss. The deterioration in mental abilities and brain function
appears to be
irreversible, and may eventually lead to death.
Alzheimer's disease is actually a family of related neurodegenerative
diseases.
One feature of Alzheimer's disease and other such neurodegenerative diseases
is the
appearance and accumulation of fibrous proteinaceous structures, commonly
known as
neurofibrillary tangles or senile plaques. Neurofilament (NF) protein is one
constituent
of neurofibrillary tangles. NF proteins may form filaments that can give rise
to
neurofibrillary tangles, for example, when the NF protein is
hyperphosphorylated. Beta-
amyloid, a protein containing about 42 amino acids, is one important component
of
certain senile plaques.
Causes of Alzheimer's disease include, genetic factors (for instance, certain
genes
on chromosomes l, 14, 19, and 21 have been implicated in increased
susceptibility to
Alzheimer's disease), or environmental factors, especially greater than normal
aluminum
concentrations. Some studies have shown that increased aluminum concentrations
within the brain may be associated with neurofibrillary tangles or senile
plaques.
Aluminum may appear, for example, complexed with beta-amyloid or neurofilament
2o protein. Certain studies have suggested a link between the aluminum found
in water
supplies and the incidence of Alzheimer's disease. Aluminum may also arise
from
pharmaceuticals or other compounds, such as antacid tablets. Aluminum may be
found
in the body complexed to other species such as organic species, or dissolved
in solution
(e.g., within the blood or the cerebrospinal fluid). For example, the aluminum
may be
present as A13+, Al(OH)3, A1203, or Al2(S04)3, etc.
SUMMARY OF THE INVENTION
This invention generally relates to the treatment and/or prevention of
diseases
characterized by the presence of metal ions, such as Alzheimer's disease. The
subject
3o matter of this invention involves, in some cases, interrelated products,
alternative
solutions to a particular problem and/or a plurality of different uses of one
or more
systems and/or articles.
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In one aspect, the invention includes a composition. In one set of
embodiments,
the composition, or at least a portion thereof, is able to enter an organ,
e.g., the brain
through transport across the blood-brain barrier. In some cases, the
composition also
includes a pharmaceutically acceptable carrier.
In certain embodiments, the composition includes at least one of a silanol, a
silandiol, a silantriol, and/or a compound able to form at least one of a
silanol, silandiol,
or a silantriol, e.g., upon exposure to physiological conditions. Such
compounds may
include, for example, a halogenated organosilicon compound or a cyclic
organosilicon
compound. In some cases, the compound is unable to significantly polymerize in
to solution. In another set of embodiments, at least 50%, at least 75%, at
least 90%, at least
95%, at least 97%, or at least 99% of the compound is able to retain a
monomeric
structure ifz vivo.
In one set of embodiments, the composition includes a compound having a
structure:
J~~
N
J~~ Y~~ ~J~s
Z~
N
15 J~°~ ~y~~ ~Z~
or a salt thereof, where each of Zl and ZZ independently is one of H, X, R,
OH, ORI, or
NJIJ2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, RI comprising at least one carbon atom, and JI and JZ each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
20 or a sulfur atom. Each of Yl and YZ is an moiety interconnecting Si and an
N (for
example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.). Each of Jlo,
Ji y JI2, and
J13 independently is H or comprises at least one of a carbon atom, a nitrogen
atom, an
oxygen atom, or a sulfur atom. In one embodiment, each of Jr°, J11,
JI2, and J13 is
independently hydrogen, an alkyl, or an aryl. In another embodiment, at least
one of Jlo,
25 Jl l, J12, and J13 is an alleyl having no more than three or four carbon
atoms. In yet
another embodiment, at least one of Yl and YZ has a structure:
Y~
where Y3 may include a hydrogen or a non-hydrogen atom. In still another
embodiment,
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Y3 comprises a hydrophobic moiety. As used herein in reference to various
chemical
structures, the symbol S indicates where a chemical structure is attached to a
parent
chemical structure, as is readily understood by those of ordinary skill in the
art. For
example, in the above structure, for at least one of Yl and Y2, the two ~
symbols indicate
where the above structure respectively attaches to N and Si in the parent
chemical
structure immediately preceding the above structure.
In another set of embodiments, the composition includes a silicon compound
comprising an aminoalkyl moiety. In one embodiment, the compound has a
structure:
z~
z, J,o z3~ li Jgio
ZswSi +N~J~z Z2~ \N/J
12
Z2~ ~Y/ \J~~ or J~~
to or a salt thereof, where each of Zl, Z2, and Z3 is independently one of H,
X, R, OH, ORI,
or NJIJZ, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, and Rl comprising at least one carbon atom. Each J
independently is H
or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom,
or a sulfur
atom, and Y is a moiety interconnecting Si and N (for example, an alkyl
moiety, an aryl
15 moiety, a cyclic moiety, etc.).
In still another set of embodiments, a composition of the invention includes a
compound having a structure:
z~
2/ li\ 34
Z Z ,
or a salt thereof, where each of ZI, Z2, Z3, and Z4 independently is one of H,
X, R, OH,
2o ORI, or NJ1J2, with R comprising at least one carbon atom, X being a
halogen or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and J2 each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. The compound may include at least one carbon atom, i.e., at
least one
of ZI, Z2, Z3, and Z4 comprises at least one carbon atom. In certain
embodiments, Zl, Z2,
2s Z3, and Z4 are not all, simultaneously, one of H or R; and Zl, Z2, Z3, and
Z4 are not all
simultaneously acetate.
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In another set of embodiments, the compound may have a structure such as:
E~
A~ \Si~ A/ \Si'~
\EZ \Z2 or ~E~s \Z2
or a salt thereof, where each of Zl and Z2 independently is one of H, X, R,
OH, ORI, or
NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
s pseudohalogen, R1 comprising at least one carbon atom, and Jl and J2 each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. In this structure, A is a moiety including at least one of a
carbon atom
and a silicon atom. Each of El and E2 (where applicable) independently is
either (a) one
of O and NJ3, or (b) absent such that Si is covalently bonded to moiety A. J3
15 H or
l0 comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom,
or a sulfur
atom. In certain instances, E1 and E2 (where applicable) are not both absent.
In yet another set of embodiments, a composition of the invention includes
cyclic
organosilicon compound, i.e., a cyclic organic compound containing at least
one silicon
atom. For example, the cyclic organosilicon compound may have a structure such
as:
z~
0
Z /S ~ /A Z S ~ /A I \Si~
15 ZZ Z O O A~~ \AZ
O
O\ ~O~ ~O~ A\
I1~SI\O/A2 Si\OAA I2~SI\O/A3 A\O~Si\O~AZ
In these structures, each A independently is a moiety having at least one of a
carbon
atom and a silicon atom, and each Z independently is one of H, X, R, OH, ORI,
or NJ1J2,
with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, Rl
20 comprising at least one carbon atom, and JI and J2 each independently being
H, or
comprising at least one of a caxbon atom, a nitrogen atom, an oxygen atom, or
a sulfur
atom. In some cases, the composition may include a salt of any of the above-
described
structures.
In still another set of embodiments, a composition of the invention comprises
a
25 compound having at least two silicon atoms. In one embodiment, the compound
has a
structure:
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z' z4
zs
~~ si~Y/si~ZS ~
or a salt thereof, where each of Zl, Z2, Z3, Z4, Z5, and Z~ independently is
one of H, X, R,
OH, ORI, or NJtJ2, with R comprising at least one carbon atom, X being a
halogen or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and J2 each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. In another embodiment, the composition includes a polymer
having a
repeat unit comprising at least one silicon atom. In yet another embodiment,
the
compound may have a structure such as:
E~'y~-Es
i~Za
ZZ Z5 or EZ-Yz-E4
1o or a salt thereof, where each of Y, Y1 and Y2 independently is an
interconnecting moiety
comprising at least one carbon atom (for example, an alkyl moiety, an aryl
moiety, a
cyclic moiety, etc.), and each of Zl, Z2, Z3, Zø, Z5, and Z6 independently is
one of H, X,
R, OH, ORI, or NJrJ2, with R comprising at least one carbon atom, X being a
halogen or
a pseudohalogen, RI comprising at least one carbon atom, and Jl and J2 each
15 independently being H, or comprising at least one of a carbon atom, a
nitrogen atom, an
oxygen atom, or a sulfur atom. Each of El, EZ, E3, and E4 independently is
either (a) one
of O and NJ3, or (b) absent such that a Si is covalently bonded to a Y moiety.
J3 can be
H or comprise at least one of a carbon atom, a nitrogen atom, an oxygen atom,
or a sulfur
atom. Typically, at least one E moiety is present within the structure.
2o In another set of embodiments, a compound of the invention includes a
chelating
agent able to bind to aluminum or another metal ion (or is able to form a
chelating agent
able to bond to aluminum or another metal ion). In one embodiment, a compound
of the
invention has a structure:
n
X-Y or X-Y
25 where X is a chelating agent able to bond to aluminum or another metal ion,
or is able to
form a chelating agent able to bond to aluminum or another metal ion.
Additionally, Y is
a structure able to facilitate transport of the compound (or a portion
thereof) across the
blood brain-barrier, the structure ~ comprises at least one chemical bond, and
the
structure - is a moiety that can be hydrolyzed under physiological conditions,
e.g.,
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within the brain or within the bloodstream, for example, to OH. In some cases,
the
chelating agent may be any agent able to bind or otherwise immobilize an ion,
for
example, so that it becomes complexed or otherwise bound to the chelating
agent instead
of remaining free in solution.
In another aspect, the invention is a method. In one set of embodiments, the
method includes administering, to a subject, a therapeutically effective
amount of a
composition comprising at least one of a silanol compound, a silandiol
compound, a
silantriol compound, a cyclic organosilicon compound, and/or a compound able
to be
hydrolyzed within the subject to at least one of a silanol compound, a
silandiol
1o compound, or a silantriol compound. In another set of embodiments, the
method
includes administering, to a subject, one or more of the compounds described
above. In
some cases, the subject is susceptible to or exhibits symptoms of Alzheimer's
disease. In
other cases, the subject is susceptible to or exhibits symptoms of a disease
characterized
by an excess of an ion such as a metal ion. In certain cases, the subject is
not otherwise
15 indicated for treatment with the composition. For example, the subject may
not be
indicated as having a disease treatable by the inhibition of leukocyte
elastase.
In some embodiments, a compound of the invention is able to bind to (or
otherwise interact with) aluminum and/or other metal ions such as divalent or
trivalent
metal ions, and/or is able to be hydrolyzed within the subject to form a
compound able to
2o bind to aluminum and/or other metal ions. In certain embodiments, the
organosilicon
compound, or at least a portion thereof, is able to enter an organ, e.g., the
brain through
transport across the blood-brain barrier. In other embodiments, however, the
organosilicon compound is not able to enter an organ such as the brain, but
instead,
remains in circulation in the bloodstream, for example, to remove or sequester
aluminum
25 or other ions within the blood before they enter the brain or other organs.
The
composition may also include a pharmaceutically acceptable carrier in certain
cases.
In another set of embodiments, the method includes administering, to a
subject, a
therapeutically effective amount of a composition comprising a compound having
a
structure:
z~ z~
[ Z3
SI Si/
30 ~ \ZZ or ~ \ZZ
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_g_
or a salt thereof, where each of Zl, Z2, and Z3 independently is one of H, X,
R, OH, OR1,
or NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and JZ each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. For clarity, in any of the chemical structures described
herein, such as
in the above-described chemical structures, not aII of the atoms bonded to
silicon are
drawn. In some cases, the subject is susceptible to or exhibits symptoms of
Alzheimer's
disease or other disease characterized by an excess of metal ions. The
structure
indicates a pouion of the compound that can be positively charged when the
compound
1o is located within the subject, for example, in an active site. In one
embodiment, the
subject is not otherwise indicated for treatment with the composition. In
another
embodiment, the structure ~ is a portion of the compound that has a structure
that
allows the compound, or at least a portion thereof, to enter into an organ, or
cross the
blood-brain barrier.
15 In one set of embodiments, the method includes administering to a subject a
composition that includes a compound able to be converted, within the subject,
into a
form able to bind aluminum and/or other metal ions such as divalent or
trivalent metal
ions, e.g., through hydrolysis. In another set of embodiments, the method
includes
administering, to a subject, a therapeutically effective amount of a
composition including
2o a compound able to cross the blood-brain barrier and/or bind aluminum
and/or other
metal ions.
In another set of embodiments, the method includes administering, to a
subject, a
therapeutically effective amount of a composition comprising a compound
comprising,
within the molecular structure of the compound, at least two silicon atoms. In
one
25 embodiment, the compound can have a molecular weight of at least about 100
g/mol, at
least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at
least about
500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about
800 g/mol, at
least about 900 g/mol, at least about 1000 g/mol, or more in some cases. In
another
embodiment, the compound is a salt.
3o In yet another set of embodiments, the method includes administering, to a
subject, a therapeutically effective amount of a composition comprising a
compound
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having, within the molecular structure of the compound, a silicon atom and a
nitrogen
atom.
In still another set of embodiments, the method is a method of chelating
metals i~
vivo. In one embodiment, the method includes administering, to a subject, a
therapeutically effective amount of a composition comprising a silicon polymer
and, in
some cases, a pharmaceutically acceptable carrier. In some instances, the
silicon
polymer may be hydroxylated and/or halogenated.
In another set of embodiments, the method is a method of facilitating the
reversion of a protein having a non-functional or a dysfunctional conformation
(i.e.,
to functioning at a less than physiologically normal level) to a functional
conformation.
The method, in one embodiment, includes the step of introducing a compound
comprising silicon into a subject, where the subject has, or is suspected of
having, a
disease or condition characterized by having a protein, a lipid, or a sugar
bound to one or
more metal atoms. The protein, lipid, or sugar may have a non-functional or a
dysfunctional conformation when so bound to the one or more metal atoms. The
method
can also include allowing at least some of the metal atoms to be transferred
from the
protein, lipid, or sugar to the silicon compound. In some cases, the silicon
polymer may
be hydroxylated and/or halogenated.
In yet another set of embodiments, the method includes administering, to a
neurological system of a subject susceptible to or exhibiting symptoms of
Alzheimer's
disease, a therapeutically effective amount of a composition comprising a
compound
having a silicon atom. In one embodiment, the composition includes a compound
having
a structure:
z~
Z~SI~ 34
2s or a salt thereof, where each of Zl, Z2, Z3, and Z4 independently is one of
H, X, R, OH,
ORI, or NJ1J2, with R comprising at least one carbon atom, X being a halogen
or a
pseudohalogen, RI comprising at least one carbon atom, and Jl and JZ each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. In some cases, one, two, three, or four of ZI, Z2, Z3, and
Z4 may each
be OH and/or acetate. In another embodiment, the composition includes a
silicate, such
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as sodium silicate, and/or a metasilicate, such as sodium metasilicate, or the
like. In yet
another embodiment, the composition includes a silicon salt.
In another aspect, the invention includes the use of a composition in the
manufacture of a medicament for treatment of diseases such as Alzheimer's
disease
characterized by the presence of metal ions. In one set of embodiments, the
composition
comprises one or more of the compounds described above. It should be
understood that
everywhere a method of treating a subject with a composition is described
herein, the
invention also involves, in another aspect, the use of that composition in the
manufacture
of a medicament for the treatment of the subject.
Io In still another aspect, the invention is directed to a method of making
any of the
embodiments described herein. In yet another aspect, the invention is directed
to a
method of using any of the embodiments described herein. In another aspect,
the
invention is directed to a method of promoting any of the embodiments
described herein.
Other advantages, novel features, and objects of the invention will become
is apparent from the following detailed description of non-limiting
embodiments of the
invention when considered in conjunction with the accompanying drawings, which
are
schematic and which are not intended to be drawn to scale. In the figures,
each identical
or nearly identical component that is illustrated in various figures typically
is represented
by a single numeral. For purposes of clarity, not every component is labeled
in every
2o figure, nor is every component of each embodiment of the invention shown
where
illustration is not necessary to allow those of ordinary slcill in the art to
understand the
invention. In cases where the present specification and a document
incorporated by
reference include conflicting disclosure, the present specification shall
control.
25 BRIEF DESCRIPTION OF THE DRAWINGS
Non-limiting embodiments of the present invention will be described by way of
example with reference to the accompanying drawings in which:
Fig. 1 illustrates a neurofilament sequence (SEQ ID NO: 1);
Figs. 2A-2U illustrate various chemical structures useful in the invention;
3o Figs. 3A-3D illustrate the effect of sodium metasilicate hydrate on the
neurofilament of Fig. I, as indicated by circular dichroism (CD) data plotted
as ellipticity
vs. wavelength;
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Figs. 4A-4E illustrate the effect of sodimn orthosilicate on the neurofilament
of
Fig. l, as indicated by CD data;
Figs. SA-SF illustrate the effect of 3-aminopropylsilantriol on the
neurofilament
of Fig. l, as indicated by CD data;
Figs. 6A-6D illustrate comparative CD data for sodium orthosilicate versus 3-
aminopropylsilantriol;
Figs. 7A-7D illustrate the effect of 3-cyanopropyltrichlorosilane on the
neurofilament of Fig. l, as indicated by CD data;
Figs. 8A-8D illustrate the effect of hexylmethyldichlorosilane on the
to neurofilament of Fig. l, as indicated by CD data;
Figs. 9A-9D illustrate the effect of methylphenyldichlorosilane on the
neurofilament of Fig.;l, as indicated by CD data;
Figs. l0A-lOD illustrate the effect of dichlorodiethylsilane on the
neurofilament
of Fig. 1, as indicated by CD data;
i5 Figs. 1 lA-1 lE illustrate the effect of dichlorodiisopropylsilane on the
neurofilament of Fig. 1, as indicated by CD data;
Figs. 12A-12E illustrate the effect of (dichloro)methylsilylbutyronitrile on
the
neurofilament of Fig. 1, as indicated by CD data;
Fig. 13 illustrates the effect of aluminum on human amyloid beta-protein, as
2o illustrated by CD data;
Fig. 14 illustrates the effect of 3-cyanopropyltrichlorosilane on the amyloid
protein, as illustrated by CD data;
Fig. 15 illustrates the effect of dichlorodiethylsilane on the amyloid
protein, as
illustrated by CD data;
25 Fig. 16 illustrates the effect of dichlorodiisopropylsilane on the amyloid
protein,
as illustrated by CD data;
Fig. 17 illustrates the effect of (dichloro)ethyhnethylsilane on the amyloid
protein, as illustrated by CD data;
Fig. 18 illustrates the effect of hexylmethyldichlorosilane on the amyloid
protein,
3o as illustrated by CD data;
Fig. 19 illustrates the effect of (dichloro)methylsilylbutyronitrile on the
amyloid
protein, as illustrated by CD data;
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Fig. 20 illustrates the effect of dichlorosilacyclobutane on the amyloid
protein, as
illustrated by CD data;
Fig. 21 illustrates the effect of I,7-dioxa-6-sila-spiro[5.5]undecane on the
amyloid protein, as illustrated by CD data;
Fig. 22 illustrates the effect of sodium orthosilicate on the amyloid protein,
as
illustrated by CD data;
Fig. 23 illustrates the effect of triethoxysilylbutyronitrile on the amyloid
protein,
as illustrated by CD data;
Fig. 24 illustrates the effect of triethoxysilylpropionitrile on the amyloid
protein,
1o as illustrated by CD data;
Fig. 25 illustrates the effect of trihydroxysilylpropylmethyl phosphonate on
the
amyloid protein, as illustrated by CD data;
Fig. 26 illustrates the effect of triethylsilanol on the amyloid protein, as
illustrated
by CD data; and
15 Fig. 27 illustrates the effect of tetrakis(dimethylamino)silane on the
amyloid
protein, as illustrated by CD data;
Fig. 28 illustrates the effect of tetraacetooxysilane on the amyloid protein,
as
illustrated by CD data;
Figs. 29A-29B illustrate transport of certain organosilicon compounds of the
2o invention across Caco-2 cells; and
Fig. 30 illustrates molecular transport of certain organosilicon compounds of
the
invention across bMVEC cells.
DETAILED DESCRTPTION
25 The present invention generally relates to the treatment and/or prevention
of
Alzheimer's disease, other neurodegenerative diseases, and/or diseases
characterized by
the presence of certain metal ions, by using certain compositions including
organosilicon
compounds. A composition of the invention may be administered to a mammal,
such as
a human. In some cases, the composition may include a silanol, a silandiol, a
silantriol,
30 or a cyclic organosilane, and/or be able to form a silanol, a silandiol, or
a silantriol upon
exposure to physiological conditions such as are found in the blood, in the
stomach
and/or gastrointestinal tract, or in the brain or other organ. In certain
cases, the
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organosilicon compound may be bound to a moiety able to be transported across
the
blood-brain barrier into the brain, for example, an amino acid, a peptide, a
protein, a
virus, etc. The organosilicon compound may also be labeled (e.g.,
fluorescently or
xadioactively) in certain instances. In some embodiments, the composition, or
a portion
thereof, may sequester aluminum or other ions, for example, by
electrostatically binding
to aluminum ions. The composition may also include other functionalities such
as
amines, certain alkyl and/or aryl moieties (including substituted alkyls
and/or aryls), or
hydrophobic moieties, for example, to facilitate transport of the
organosilicon compound
through the blood-brain barrier.
1o The following applications are incorporated herein by reference: U.S.
Patent No.
5,523,295, issued June 4, 1996, entitled "Method fox Treating and Preventing
Alzheimer's Disease," by G. D. Fasman; U.S. Provisional Patent Application
Serial No.
60/427,203, filed November 18, 2002, entitled "Compositions for Treating and
Preventing Alzheimer's Disease," by O. Friedman, et al.; U.S. Provisional
Patent
Application Serial No. 60/427,1 OS, filed November I 8, 2002, entitled
"Compositions for
Treating and Preventing Alzheimer's Disease," by O. Friedman, et al.; U.S.
Provisional
Patent Application Serial No. 60/427,104, filed November 18, 2002, entitled
"Compositions for Treating and Preventing Alzheimer's Disease," by O.
Friedman, et
al.; U.S. Provisional Patent Application Serial No. 60/427,201, filed November
I8,
2002, entitled "Chelating Agents," by O. Friedman, et al.; and U.S.
Provisional Patent
Application Serial No. 60/456,345, filed March 20, 2003, entitled
"Compositions for
Treating and/or Preventing Diseases Characterized by the Presence of Metal
Ions," by O.
Friedman, et al.
The indefinite articles "a" and "an," as used herein in the specification and
in the
claims, unless clearly indicated to the contrary, should be understood to mean
"at least
one."
As used herein, "or" is understood to mean inclusively, i.e., the inclusion of
at
least one, but including more than one, of a number or a list of elements.
Only terms
clearly indicated to the contrary, such as "exclusively" or "exactly one of,"
will refer to
3o the inclusion of exactly one element of a number or list of elements.
The term "determining," as used herein, generally refers to the analysis of a
species, for example, quantitatively or qualitatively, and/or the detection of
the presence
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or absence of the species. "Determining" may also refer to the analysis of an
interaction
between two or more species, for example, quantitatively or qualitatively,
and/or by
detecting the presence or absence of the interaction.
As used herein, a material is "able to cross the blood-brain barrier" if it is
capable
of being transported (passively or actively) from the blood to the brain or
central nervous
system in vivo under physiological conditions using endogenously available
transport
processes such as diffusion or certain endogenous transpou systems. For
example, a
composition of the invention (or a portion thereof) may include a sugar or a
peptide,
and/or be able to be substituted as a substrate (i.e., a mimic) in a sugar
and/or a peptide
1o transport system of the blood-brain barrier (e.g., endogenous transport
proteins), thus
allowing transport of the composition across the blood-brain barrier to occur.
As used
herein, the "blood-brain barrier" is given its ordinary meaning as used in the
art, i.e., the
cellular barrier separating the bloodstream from the "neurological system,"
i.e., the brain
and central nervous system, including the spinal cord.
"Treatment of Alzheimer's disease," as used herein, includes preventing,
arresting, altering, and/or reversing formation of neurofibrillary tangles
and/or senile
plaques within the brain, and may be performed on subjects "in need of such
treatment,"
i.e., a subject that exhibits symptoms of Alzheimer's disease, a subject
susceptible to or
otherwise at increased risk for Alzheimer's disease, or a subject not
exhibiting symptoms
of Alzheimer's disease, but for whom it is desired to decrease the risk of
Alzheimer's
disease (e.g., a vaccination or a prophylactic treatment). The term "patient"
or "subject"
as used herein includes mammals such as humans, as well as non-human mammals
such
as non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, rabbits,
or rodents
such as mice or rats.
It should be understood that any of the compositions or methods described
herein
in reference to Alzheimer's disease can also be used, in some cases, to treat
other
diseases characterized by an excess of metal ions. As used herein, a disease
"characterized by an excess of an ion" includes any disease where an excess of
an ion
(e.g., a metal ion) within an organ or a system of the body may lead to health-
related
3o problems. Examples of such ions include, but are not limited to, iron,
lead, aluminum,
magnesium, calcium, mercury, strontium, beryllium, cobalt, zinc, nickel,
arsenic, etc.
The ions may be divalent or trivalent (i.e., having a net charge of ~2 or ~3,
respectively)
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in certain instances. .In some cases, the disease may result in misfolded
proteins, due to
the presence of excess ions. As one example, Alzheimer's disease can be
characterized
by an excess of aluminum ions in the brain. Other brain diseases which may be
characterized by an excess of ions include, for example, certain prion
diseases such as
s transmissible spongiform encephalopathy or Creutzfeldt-Jakob disease. Other
diseases
where an excess of ions such as metal ions has been implicated include
Parkinson's
disease, various homeostatic diseases, cardiac arrhythmia, various central
nervous
system (CNS) disorders, blood plasma imbalances, dermatitis, Gerstmann-
Staussler-
Scheinker disorder, familial insomnia, Menkes's syndrome, or heavy metal
toxicity or
1o poisoning. In some cases, the disease may be created by environmental
factors, for
example, an excess of ions such as aluminum, lead or iron from the
environment. In
other cases, the disease ions may be created through diet, drinking water, on
the like.
The organ or system may be any organ or system in the body, for example,
within the
bloodstream, within the brain, liver, kidneys, skin, fatty tissue, etc. Other
diseases
15 characterized by an excess of ions may be readily identified by those of
ordinary skill in
the relevant art.
As used herein, an "amino acid" is given its ordinary meaning as used in the
field
of biochemistry. An amino acid typically has a structure:
H
HZN-C-COOH
R
2o In this structure, R may be any suitable moiety; for example, R may be a
hydrogen
atom, a methyl, or an isopropyl. A series of amino acids can be connected to
form a
peptide or a protein, by reaction of the NH2 of one amino acid with the COOH
of the
next amino acid to form a peptide (-NH-C(O)) bond. The amino acid may be a
natural
amino acid or an unnatural amino acid. As used herein, the "natural amino
acids" are the
25 20 amino acids commonly found in nature, i.e., alanine, arginine,
asparagine, aspartic
acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,
leucine, lysine,
methionine, phenylalaine, proline, serine, threonine, tryptophan, tyrosine,
and valine.
Conversely, an "unnatural amino acid" is an amino acid corresponding to the
above
structure, where the R moiety does not correspond to one of the 20 natural
amino acids.
3o In some cases, the amino acid may also be derivatized in some fashion. For
example, the
amino acid may be amidated, esterified, side moieties may be attached to the
amino acid,
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etc. Other amino acid derivatization reactions will be known to those of
ordinary slcill in
the art.
As used herein, an "alkyl" is given its ordinary meaning as used in the field
of
organic chemistry. Alkyl or aliphatic moieties may contain a number of carbon
atoms.
The moieties may include, for example, between 1 and 15 carbon atoms, between
1 and
carbon atoms, or between 1 and 5 carbon atoms. In certain embodiments, the
alkyl
moiety will have less than 10 carbon atoms, less than 6 carbon atoms, less
than 5 carbon
atoms, less than 4 carbon atoms, or less than 3 carbon atoms. In some
embodiments of
the invention, alkyl chains having a certain size may be used to control the
10 hydrophobicity of the composition. The carbon atoms may be arranged in an
appropriate
configuration within the alkyl moiety, for example, as a straight chain (i.e.,
an h-alkyl
such as methyl "(Me"), ethyl ("Et"), propyl ("Pr"), butyl ("Bu"), pentyl
("Pe"), or hexyl
("Hx")) or a branched chain (e.g., a tent-butyl moiety, or an isoalkyl moiety
such as an
isopropyl moiety). The alkyl moiety may contain zero or one or more double or
triple
1s bonds within its structure, for example, as in an alkene, an alkyne, an
alkadiene, an
alkadiyne, an alkynene, etc. The alkyl moiety may also contain substituents in
some
cases. For example, the alkyl moiety may contain a halogen, an alkoxy (e.g.,
methoxy,
ethoxy, or propoxy), an amine (e.g., a primary, secondary, tertiary, or
quaternary amine),
an ether, a carbonyl (e.g., an acetyl ("Ac") moiety) or a hydroxide as a
substituent (i.e., a
"substituted alkyl"). If more than one substituent is present, then the
substituents may
each be the same or different. In some cases, the alkyl moiety includes only
carbon and
hydrogen atoms; however, in other cases, the atoms within the alkyl moiety may
also
include nitrogen atoms, oxygen atoms, sulfur atoms, silicon atoms, or any
other suitable
atom.
Similarly, a "cyclic" moiety, as used herein, is given its ordinary definition
as
used in the field of organic chemistry, i.e., a moiety that contains at least
one ring of
atoms, and may contain more than one ring of atoms. That is, a cyclic moiety
has at least
one chain of atoms that does not have a terminal end. The chain may have, for
example,
three, four, five, six, seven, eight, nine, or ten or more atoms arranged in a
ring. In some
3o embodiments, the cyclic moiety has a maximum size of at most ten atoms, at
most eight
atoms, or at most seven atoms. In some cases, the cyclic moiety includes only
carbon
atoms within the ring of the cyclic moiety; however, in other cases, the atoms
within the
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ring may also include nitrogen atoms, oxygen atoms, sulfur atoms, silicon
atoms, or any
other atom able to covalently bond to at least two different atoms (i.e., a
"heterocyclic"
moiety). If the cyclic moiety contains more than one ring, the rings may be
arranged in
any orientation with respect to each other, e.g., the rings may be fused
(i.e., at least two
s rings have more than one atom in common, for example, as in bicyclic
moieties, tricyclic
moieties, etc.), spiro (i.e., two rings have only one atom in common), a ring
may be a
substituent on another ring, two or more rings may be connected through an
alkyl
moiety, etc. The cyclic moiety may contain zero or one or more double or
triple bonds
within its structure, for example, as in a cycloalkene, a cycloallcyne, a
cycloalkadiene, an
to aromatic moiety, or the like. The terms "aromatic" or "aryl" moieties are
given their
ordinary meaning as used in the art, e.g., where at least two or more atoms of
the moiety
participate in delocalized pi bonding. Aryl moieties which include one or more
non-
carbon atoms (e.g., nitrogen) participating in delocalized pi bonding are
"heteroaryl"
moieties.
1s A "silicon compound," as used herein, includes any chemical compound that
contains at least one silicon atom. The silicon compound may be water-soluble,
lipid-
soluble, or exhibit amphiphillic properties, e.g., when located within a
subject. An
"organosilicon compound," as used herein, is a compound that includes at least
one
silicon atom bonded to an organic moiety, such as an alkyl, an aryl, an
alkoxy, a
2o cycloallcyl, an amine (primary, secondary, tertiary, or quaternary), etc.
An
"organosilicon composition" includes at least one organosilicon compound and
may
include other compounds as well, for example, other physiologically active
compounds
and/or pharmaceutically acceptable carriers such as those further described
below. In
some embodiments, the silicon atom within the organosilicon compound may be
25 hypercoordinated (i.e., the silicon atom may have a valency of 5 or 6).
In one set of embodiments, the silicon compound includes one or more
"hydrolyzable" moieties (for example, a moiety that can by hydrolyzed under
physiological conditions, spontaneously and/or through metabolic processes,
e.g., to a
hydroxide moiety), such as halogens, hydroxides, alkoxides, esters, ethers,
etc.
3o Examples include, but are not limited to, a halosilane, a dihalosilane, a
trihalosilane, a
silanol, a dihalosilanol, a halosilandiol, a silantriol, a halosilanol, etc.
Terms such as
"silanol," "silandiol," and "halosilane" are given their ordinary meanings as
used in the
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field of chemistry. For instance, a "silandiol" is a compound which includes
two
hydroxide moieties covalently bonded to a silicon atom, and a "silantriol" is
a compound
which includes three hydroxide moieties covalently bonded to a silicon atom.
Similarly,
a "dihalosilane" (e.g., dichlorosilane or bromochlorosilane) is a compound
that includes
two halogen atoms (as further defined below) each bonded to a silicon atom
(i.e., where
the halogen atoms may be the same or different), and a "halosilanol" is a
compound that
includes a halogen and a hydroxide moiety each bonded to a silicon atom within
the
compound. Terms such as "trihalosilane," "dihalosilanol," and "halodisilanol"
are
similarly defined. The term "halogen," (or "halo='), as used herein, includes
halogen-
to group atoms as ordinarily used in the field of chemistry (e.g., fluorine,
chlorine, bromine,
or iodine). As used herein, "pseudohalogens" are moieties that are not halogen
atoms,
but have properties similar to halogen compounds. Examples of pseudohalogens
include
CN, SCN, NCO, etc., and other hydrolyzable moieties that can form labile bonds
with
silicon (e.g., imidazoles, triazoles, tetrazoles, etc). In many cases, a
pseudohalogen
moiety can be substituted for a halogen atom in any of the structures
described herein.
The organosilicon compounds of the present invention, in one set of
embodiments, may inhibit and/or reverse interaction between ions such as
aluminum
ions and physiological (or neurological) components of the brain or other
organs, such as
beta-amyloid or other amyloid compounds, neurofilament proteins, etc. For
example,
2o certain types of amyloid proteins may be found in the liver or in muscle
tissue. The
compounds may inhibit and/or reverse such interactions anywhere within the
body, e.g.,
within the brain or other organ, within the blood-brain barrier, within the
bloodstream,
etc. The term "inhibit" includes inhibition which occurs before and/or after
the
aluminum (or other metal ion) complexes with the component. The inhibition may
be
partial or complete inhibition. One simple test to illustrate the efficacy of
the
compositions of the invention is to add the composition to a solution
containing a a
component such as a suitable disease marker, and determine if the added
composition is
able to prevent or reduce changes in the structure and/or conformation of the
component
or marker when the solution is exposed to aluminum. As an example, for
Alzheimer's
3o disease, a suitable marker for the disease may be a beta-amyloid or a
neurofilament
protein (or a cell able to produce beta-amyloid or a neurofilament protein)
that is
sensitive to aluminum, i.e., where the structure and/or conformation of the
marker is
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altered upon exposure to aluminum). The composition may be added before or
after the
marker is exposed to aluminum or other ions. An example of this process is
discussed in
Example 1. Those of ordinary skill in the art will understand that "aluminum,"
as used
herein, refers to any form of aluminum that may appear in the body, for
example, as
aluminum particles, aluminum oxide particles, aluminum ions (A13+), Al(OH)3,
A1203,
A12(S04)3, etc. The aluminum may arise from any environmental source, for
example,
dissolved within drinking water; from aluminum pots, pans, pipes, utensils, or
tools;
from dust; from components of medical devices; from medications; from jewelry;
from
aerosols; from deodorants and other products applied to the skin; from
aluminum cans,
to etc.
In some embodiments, however, the organosilicon compounds of the invention
are not able to enter the brain or other organ. In such embodiments, the
organosilicon
compounds may remain where they were introduced into the body, or the
organosilicon
compounds may remain in circulation in the bloodstream. As one example, if a
is compound is injected directly into the brain (e.g., as further described
below), the
compound may be unable to cross the blood-brain barrier and hence is able to
remain
within the brain. As another example, a compound of the invention may be
introduced
into systemic circulation, to remove or sequester aluminum or other ions
within the
blood before they enter the brain or other organs.
2o Compositions of the invention, according to one set of embodiments, may be
administered to a subject so as to treat (e.g., reverse), prevent, and/or
reduce the
formation and/or growth of neurofibrillary tangles or senile plaques within
the brain. In
persons with Alzheimer's disease or other neurodegenerative diseases, the beta-
amyloid
and/or neurofilament proteins found in senile plaques and neurofibrillary
tangles may
25 become, in some cases, phosphorylated and/or complexed in the presence of
metal ions
such as aluminum and/or assume a dysfunctional or a nonfunctional conformation
(e.g., a
structure that lacks proper activity, or a structure indicative of a diseased
state) such as a
beta-sheet. The beta-sheet or other nonfunctional/dysfunctional conformation
within
these proteins may cause the beta-amyloid and/or neurofilament proteins to
become
3o insoluble and/or to precipitate, which may thereby cause the formation of
neurofibrillary
tangles and/or senile plaques within the brain.
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In one set of embodiments, a composition of the present invention may bind to
or
otherwise sequester ions such as metal ions within the body. In one set of
embodiments,
the ion is divalent or trivalent. The ion may be present within the body, or
within an
organ or system within the body, in an excess concentration (e.g.,
significantly above a
concentration that is physiologically desirable). In some cases, the
composition may
sequester the ion by interaction of the ion with a charged portion of the
composition, e.g.,
of the opposite charge.
In some cases, the composition may allow a molecule or structure affected by
an
excess of metal ions to revert back to its original conformation, or the
composition may
to prevent the formation of nonfunctional or deformed structures, for example,
as in a
protein that has been denatured, or improperly folded or configured, due to
the presence
of an excess of metal ions. Thus, compositions of the invention may be
determined by
their ability to allow a molecule or structure to revert back to its original
conformation,
etc. The composition may bind and/or sequester the excess ion, which may
prevent,
15 inhibit, and/or reduce interaction of the ion with the molecule or
structure. For example,
the presence of the compositions of the invention in the brain may allow
certain
neurofilament proteins to revert back to their original functional structures,
and/or
prevent the formation of the beta-sheet conformation or other nonfunctional or
dysfunctional structures within the neurofilament proteins. The organosilicon
compound
2o may also bind any aluminum (or other metal ions) present within the brain
or other
organ, which may cause at least some sequestering of aluminum or other metal
ions,
preventing and/or reducing interaction of aluminum with other components of
the brain
or other organ, for example, with beta-amyloid or neurofilament proteins. The
interaction of the composition with aluminum or other metal ions may be, for
instance,
25 via an ionic interaction, a hydrogen bond interaction, a van der Waals
interaction, a metal
ligand interaction, a dative interaction, a hydrophobic interaction, and/or a
combination
of these. The degree of such binding can be determined by those of ordinary
skill in the
art; for example, an organosilicon composition of the invention may be mixed
with a
solution containing a known concentration of aluminum ions or other metal
ions, and the
3o resulting decrease in the concentration of free aluminum or other metal
ions in solution
(if any) may be determined or calculated using known techniques for detecting
the
dissolved ions in solution, for example, using circular dichroism (CD)
techniques, atomic
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absorption spectroscopy, mass spectroscopy, radioactive tracer measurements,
or the
like.
In some cases, an ion such as aluminum may be sequestered within the body or
the brain or other organ by the organosilicon compositions of the invention,
for instance,
by sequestering the aluminum ions with a negatively charged portion of an
organosilicon
compound. For example, the organosilicon compound may include one or more
hydroxide moieties that can become negatively charged under physiological
conditions
(i.e., deprotonated), enabling electrostatic attraction or binding of aluminum
or other
metal ions to the compound. In one set of embodiments, the organosilicon
compound
to may be a silanol, a silandiol, or a silantriol. In another set of
embodiments, the
organosilicon compound may be a silicon compound able to form a silanol, a
silandiol,
or a silantriol upon hydrolysis of the compound, for example, within the body
under
physiological conditions (e.g., at a temperature of 37 °C and/or within
a generally
aqueous environment). In some embodiments, after formation of the aluminum-
organosilicon complex (or other ionic-organosilicon complex), the complex may
also be
removed from the brain or other organ, e.g., physically removed, or otherwise
deactivated.
In one aspect, the composition includes a compound containing silicon. Silicon
compounds include, e.g., acids, salts, bases, oxides, etc., for example,
silicic acid
(H4Si04), silicon tetraacetate, sodium silicate, sodium metasilicate, etc.
Additional
examples are described below. The silicon compound may be capable of binding
to or
otherwise interacting with aluminum or other metal ions, e.g., within the
central nervous
system or other organ, or within the bloodstream, as further described below.
In one set of embodiments, the invention provides a composition comprising one
or more of the compounds shown below (numbered 1-35), optionally with a
pharmaceutically acceptable carrier:
~oH
OH OEt ~ ~ sip
HO % ~ i NHZ Et0 jSi NH2
Ho 1 Eto 2 3
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OH
CI~ li ./'CI Sip ~ CI
C! ~ ~Si \
SCI CI~Si CN
4 5 c! ~
~cl
s~~
cl
sip Si~cl
~c! 7 8 ~ ~cl 9
~i~ci
~~,-ci
CI
ei~s~
s cite 10 ~ 11 ~ 12
~,cl
CI~ li CN Sid
cW 13 cl 14 ' 15
OH
j'
cms~ Si
cW 16 / \ 17 lg
OAc OEt NMe2
/Si\ OAc ~ li\ OEt /Sid NMe2
Ac0 OAc 19 Et0 OEt 20 MeZN NMe2 21
~OH
OEt OEt ~Si~-
Et0 jSi CN Et0 ~Si
EtO 22 Eto ~cN 23
24
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oN ~H
HO S1
OOH
25 ~ 26 2~
OH O CI
HO j ~i~~\ OH CI ~ ~i~ CI ~Si~CN
HO OH 28 CI CN 29 CI 30
II IEt
CI ~Si NHZ Et0 ~Si CN Cite ~ i
cl 31 Eto ~ 32 clue RCN 33
OH
CI~ li CN HO s~~'OH
CI~ ~ 34 ~~ ~oH 35
In another set of embodiments, the composition includes a silicon compound or
an organosilicon compound, i.e., a compound including at least one silicon
atom bonded
1o to an organic moiety. In one set of embodiments, the compound may have a
structure
such as:
Z1
2/SI~ 34
Z Z ,
or a salt thereof, where each of Z1, Z2, Z3, and Z4 independently is one of H,
X, R, OH,
ORI, or NJ1J2, with R comprising at least one carbon atom, X being a halogen
or a
15 pseudohalogen (for example, a nitrite), Rl comprising at least one carbon
atom, and J'
and JZ each independently being H, or comprising at least one of a carbon
atom, a
nitrogen atom, an oxygen atom, or a sulfur atom. The compound, in this
instance,
includes at least one carbon atom, i.e., at least one of Zl, Zz, Z3, and Z4
comprises at least
one carbon atom. In certain embodiments, Zl, Z2, Z3, and Z4 are not all,
simultaneously,
20 one of H or R; and Zl, Z2, Z3, and Z4 are not all simultaneously acetate.
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In another set of embodiments, the composition includes a compound having a
structure:
z1
2~SI~
Z Z,
or a salt thereof, where each of Z1, ZZ, Z3, and Z4 independently is one of H,
X, R, OH,
ORI, or NJIJ2, with R comprising at least one carbon atom, X being a halogen
or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and JZ each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. In some cases, one, two, three, or four of Zl, Z2, Z3, and
Z4 may each
be OH and/or acetate. In another embodiment, the composition includes a
silicate, such
to as sodium silicate, and/or metasilicate, such as sodium metasilicate, or
the like.
In another set of embodiments, the compound may have a structure such as:
E1 1 N 1
a~ s~~z A~\ s~.~z
\EZ \ZZ OY \E1O \Z2
or a salt thereof, where each of Zz and Zz independently is one of H, X, R,
OH, ORI, or
NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
15 pseudohalogen, Rl comprising at least one carbon atom, and Jl and J2 each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. In this structure, A is a moiety having at least one of a
carbon atom and
a silicon atom. Each of El and EZ (where applicable) independently is either
(a) one of O
and NJ3, or (b) absent such that Si is covalently bonded to moiety A. J3 is H
or
2o comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom,
or a sulfur
atom. In certain instances, El and EZ (where applicable) are not both absent,
and Si may
be bonded to A as well as to El or E2, which is not absent.
In yet another set of embodiments, the compound may be a cyclic organosilicon
compound. In some cases, more than one ring may be present within the
compound, for
25 example, as in a bicyclic or a spiro ring system (i.e., where the rings
share one, two,
three, or more atoms). In some cases, the two rings of the bicyclic or spiro
structure may
each comprise alkyl moieties. As an example, the compound, in one embodiment,
has a
structure such as:
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- 25 -
~E~ /E\ /N~ ~E\ /N~ ~N\
A\E SyE4 A~ A~Ea Si\E~ AZ A~EZ Si~E4 AZ
J~°
A~ jSi-Z A~ jSi ASE j i=N
E~ N E2
Az-A~ -As Aa -p~~-Aa A2 -A~ -As
E~-Si- EZ N- Si-E~ N- Si- N
Z Z Z
In these structures, each Al, A2, and A3 independently is a moiety having at
least one of a
carbon atom and a silicon atom, and each of El and E2 (where applicable)
independently
is either (a) one of O and NJ3, or (b) absent such that Si is covalently
bonded to moiety
Al. Z is one of H, X, R, OH, ORI, or NJ1J2, with R comprising at least one
carbon atom,
1o X being a halogen or a pseudohalogen, and RI comprising at least one carbon
atom. In
some cases, Ei and EZ axe not both absent. E3 and E4 (where applicable) may
independently be either (a) one of O and NJ4, or (b) absent such that Si is
covalently
bonded to moiety A2. Each J independently is H or comprises at least one of a
carbon
atom, a nitrogen atom, an oxygen atom, or a sulfur atom. In some cases, the
composition
15 of the invention may include a salt of any of the above-described chemical
structures.
In some cases, the cyclic organosilicon compound may include one or more
hydrolyzable structures, for example, a compound of the invention may be
hydrolyzed to
form a silanol, a silandiol, or a silantriol, e.g., upon exposure to
physiological conditions.
For example, the cyclic organosilicon compound may include an ester or an
amine
2o moiety that is hydrolyzable to form a hydroxide, which may thus cause one
or more rings
of the cyclic organosilicon compound to open.
In still another set of embodiments, the compound may be a structure having at
least two silicon atoms. In some cases, the compound may be a polymer, for
example, a
polymer having a repeat unit comprising at least one silicon atom, as further
discussed
25 below. In some cases, the compound has a structure such as:
Z Z6 z~ E~-Y~-Es Zs
\~ i-E~-Y-Ez-S\ \
Zz~S\ ~ iwZa
ZZ Z5 or EZ-Yz-Ea
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or a salt thereof, where each of Y, Yl and Y2 independently is an
interconnecting moiety
comprising at least one carbon atom (for example, an alkyl moiety, an aryl
moiety, a
cyclic moiety, etc.), and each of Zl, Z2, Z3, Z4, Z5, and Z6 independently is
one of H, X,
R, OH, ORi, or NJ1J2, with R comprising at least one carbon atom, X being a
halogen or
a pseudohalogen, Rl comprising at least one carbon atom, and Jl and JZ each
independently being H, or comprising at least one of a carbon atom, a nitrogen
atom, an
oxygen atom, or a sulfur atom. Each of E1, E2, E3, and E4 (where applicable)
independently is either (a) one of O and NJ3, or (b) absent such that a Si is
covalently
bonded to a Y moiety. J3 can be H or comprises at least one of a carbon atom,
a nitrogen
to atom, an oxygen atom, or a sulfur atom. Typically, at least one E moiety is
present
within the structure.
In any of the above-described embodiments, any one, two, three, four, five, or
six
of Zl, ZZ, Z3, Z4, Z5, and Z6 (where applicable) may each independently be a
halogen (X),
for example, F, Cl, Br, I, etc., or a pseudohalogen. In some cases, the
halogen or
15 pseudohalogen may be hydrolyzable under physiological conditions to OH.
In another set of embodiments, any one, two, three, four, five, or six of Zl,
Z2, Z3,
Z4, Z5, and Z6 (where applicable) may each independently be a hydroxide (OH),
or an
alkoxy (ORI, where Rl comprises at least one carbon atom). The hydroxide, in
some
instances, can be deprotonated under physiological conditions (i.e., to O-).
In some
2o cases, the allcoxy may be hydrolyzable (e.g., within a subject) to form a
hydroxide. Non-
limiting examples of alkoxy moieties include methoxy (OMe), ethoxy (OEt),
propoxy
(OPr), isopropoxy, butoxy (OBu), tent-butoxy, sec-butoxy, acetoxy (OAc), etc.
The
alkoxy moieties may be substituted allcoxy moieties in some cases, for
example, a
chloromethoxy or a bromochloromethoxy moiety.
25 Any one, two, three, four, five,,or six of Zl, Z2, Z3, Z4, Z5, and Z6
(where
applicable) may each independently be a moiety comprising at least one carbon
atom in
any of the above-described embodiments. For example, R can be an alkyl (e.g.,
methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tent-butyl, pentyl,
isopentyl, hexyl,
isohexyl, heptyl, isoheptyl, octyl, isooctyl, etc.), a cycloalkyl, an aromatic
moiety (e.g.,
3o phenyl, benzyl, a substituted phenyl or benzyl, etc.), an aminoalkyl, a
hydroxyallcyl (e.g.,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxpropyl, etc.), a
cyanoallcyl
(i.e., an alkyl comprising at least one CN, such as cyanoethyl, cyanopropyl,
cyanobutyl,
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etc.). Moieties containing nitrites (e.g., ethylnitrile, proprionitrile,
butyronitrile, etc.)
may be particularly useful in some cases. Nitrite moieties may allow the
compound to
bind to metal ions such as aluminum. In some cases, the nitrite moiety may
facilitate
transport or penetration of the compound across the blood-brain barrier, e.g.,
as further
described below. In some embodiments, the alkyl moieties may further include
one or
more side moieties. The side moiety may be any non-hydrogen atom or moiety,
for
example, an alkyl moiety such as a methyl moiety or a cycloalkyl moiety. The
side
moiety (or moieties) may be chosen, for example, to allow for detection of the
compound, to allow the compound to have a certain degree of hydrophobicity or
other
to physical properties, to allow the compound to have certain metabolic
functions, to allow
the compound to have certain immunological properties, etc. In one set of
embodiments,
a hydrophobic side chain is attached to the compound, for example, an alkyl
moiety, a
cyclic moiety, or an aryl moiety. In some cases, the cyclic moiety may be an
unsaturated
structure, such as a cyclohexyl structure.
In any of the above-described embodiments, the compound can include a
phosphono moiety, i.e., a moiety having a structure:
0
I/OH
OH .
In some cases, for example, under certain physiological conditions, one or
both of the
OH moieties within the phosphono moiety may be hydrolyzed to O-. In some
instances,
2o the phosphono moiety may allow the compound to bind to metal ions such as
aluminum.
In any of the above-described embodiments, any one, two, three, four, five, or
six
of Zl, Z2, Z3, Z4, Z5, and Z6 (where applicable) may each independently
comprise a
nitrogen-containing moiety, for example, an amine, a hydroxylamine, an oxime,
a nitro
moiety, etc. As one example, the nitrogen-containing moiety may contain a
sulfur atom,
2s which may be bonded to a nitrogen atom, such as in a sulfonamide, i.e., as
in the
structure N-S02 Ar, where Ar is an aryl (including a heteroaryl) moiety (bonds
removed
for clarity). As another example, the nitrogen-containing moiety may contain
an oxygen
atom, which may be bonded to the nitrogen atom, such as in a hydoxylamine (N-
OH), an
oxime (N-OR, R comprising at least one carbon atom), or a nitro moiety (NOz).
As yet
3o another example, the nitrogen-containing moiety may contain two nitrogen
atoms, which
may be bonded to each other, such as in a hydrazide (N NH2), a substituted
hydrazide
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(N NHJ or N-NHJIJz, each J comprising at least one of a carbon atom, a
nitrogen atom,
an oxygen atom, or a sulfur atom, such as acyl, sulfonyl, etc.), or the like.
In any of the above-described embodiments, any one, two, three, four, five, or
six
of ZI, Z2, Z3, Z4, Z5, and Z6 (where applicable) may each independently have a
formula
NJ1J2, where Jl and J2 each independently is H or comprises at least one of a
carbon
atom, a nitrogen atom, an oxygen atom, or a sulfur atom. Jl and J2 each may
contain
atoms other than carbon and hydrogen atoms, for example, sulfur, nitrogen, or
oxygen.
As one example, NJ1J2 may be an amine. In some cases, the N of the amine may
be
covalently bonded to Si. In other cases, however, the N of the amine may not
be
to covalently bonded to Si, and one or more carbon atoms may connect the N of
the amine
to Si (i.e., a aminocycloalkyl moiety such as an aminoaryl moiety, or an
aminoalkyl
moiety such as an aminopropyl, an aminobutyl, an aminopentyl, etc). The amine
may be
a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.
In one set of embodiments, at least one aminoalkyl and/or aminoaryl moiety is
chosen such that the amine moiety is able to interact with one or more
hydroxide
moieties covalently bonded to a silicon atom of the compound. The interaction
of the
aminoalkyl and/or aminoaryl moiety with the hydroxide moiety (which may be
present,
for example, as OH or O-) may stabilize the compound, for example, against
degradation
or polymerization in solution (e.g., spontaneous polymerization in water) in
certain
2o instances. Significant or detectable degradation or polymerization in
solution may be
prevented, for example, by self interaction within the compound, which may
prevent or
inhibit substantial and/or stable polymerization of the compound to
neighboring
molecules. For example, the compound may have a structure, or may be
hydrolyzed or
protonated within the body to form a structure such as:
J~ J~
iJ3 Nits
A/ ~ \Jz A/ 1 \Jz
1 I 1
SI- IOH or Si-O
Where A is any alkyl and/or aryl moiety that allows substantial interaction
between the
nitrogen atom and the hydroxide to occur (indicated by ------), and each of
Jl, J2, and J3
independently is H or comprises at least one of a carbon atom, a nitrogen
atom, an
oxygen atom, or a sulfur atom. Examples of suitable alkyls include those
previously
3o described. In the above structures, not all of the atoms bonded to silicon
are drawn for
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reasons of clarity. As an example, in an aminoalkyl moiety, the aminoalkyl
moiety may
include 2, 3, 4, 5, or 6 carbon atoms between the nitrogen atom and the
silicon atom. In
some cases the aminoalkyl moiety may be aminopropyl, aminobutyl, or
aminoisobutyl,
etc. Non-limiting examples of compounds having aminoalkyl moieties include the
following:
H2N
H2N Si(OH)3 H2N Si(OH)3 Si(OH)3
H2N H2N
~Si(OH)3 'Si(OH)3
H2N
Si(OH)3
H2N
H2N H2N ~ ~Si(OH)3 v 'Si(OH)3
Si(OH)3
In some embodiments, the aminoalkyl moiety may include more than one amino
moiety, for example, as in a bis(aminoalkyl)alkyl moiety or a
tris(aminoalkyl)alkyl
moiety. Examples of compounds having such structures include, but are not
limited to:
Me3N+ Si
Me3N+ Si CMe3N+
Si
3
CMe2N ~ Et2N CMeHN
Si 3 Si 3 Si
In these structures, not all of the atoms that are bonded to silicon are
shown, for reasons
of clarity. Combinations of these and other aminoalkyl moieties are also
envisioned, for
example, a bis(dimethylaminoethyl)(trimethylaminoethyl)ethyl moiety. A further
2o example is provided by the following structures:
t12 X13
X12 X13
~N~
X11
N , Si~Z2
10 X10 ~Z1
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J12
N\J~s
J
N
J~of
In these structures, each of Z1 and ZZ independently is one of H, X, R, OH,
ORI, or
NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and J2 each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom. Each of Jl°, J11, Jlz, and J13 is independently H or
comprises at least one
of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom. In some
cases, Zl
and Z2 may each independently be a halogen or a pseudohalogen, such as
chlorine or
1o CN, or an alkoxy, such as methoxy. In certain embodiments, each of
Jl°, JII, J12, and J13
may independently be an alkyl, for example, methyl, ethyl, propyl, butyl,
pentyl, etc.
As another example, an aminoallcyl moiety of the compound may include a cyclic
structure (i.e., an aminocycloalkyl moiety), e.g., an aryl moiety, a saturated
or
unsaturated cyclic moiety, a heteroaryl moiety, etc. The aminocycloalkyl
moiety may
optionally include one or more alkyl moieties, for example, between an aryl
moiety or a
cycloalkyl moiety and the silicon atom. Non-limiting examples of
aminocycloallcyl
compounds include:
Ar-Si Ar-Ak-Si Ak2-Ar-Ak~-Si
Si
Ak-Ar-Si Ar Ar Si
N \ Si N~N/Si
~NH
Ark Si Ark
N N Si
AI,~
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N \ Si N ~ N Si
~N f/ ~N
In the above structures, each Ak independently comprises an alkyl, each Ar
independently comprises an aryl (for example, an aminoaryl), and J
independently is H
or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom,
or a sulfur
atom. In some cases, the silicon composition may include both aminoalkyl and
aminocycloalkyl moieties, including the amines previously discussed.
In one set of embodiments, the compound is an aminosilicon compound, or a salt
thereof, i.e., a compound in which a nitrogen atom is covalently bonded to a
silicon
1o atom. The compound may be, for example, a silanol, a silandiol, or a
silantriol, or a
compound able to form a silanol, a silandiol, or a silantriol upon hydrolysis,
for example,
under physiological conditions. The aminosilicon compound is cyclic in some
cases.
Non-limiting examples of cyclic aminosilicon compounds include:
J~
p N J
A~ \Si A/ \Si
\NA ~~~ . \N~ ~N~ .
A ~ ~Si A~ /S~
J N JZ N
In these structures, A is a moiety having at least one of a carbon atom and a
silicon atom
(for example, an alkyl, a cycloalkyl, an aryl, etc.), and each J independently
is H or
comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a
sulfur
atom. In the above structures, not all of the atoms bonded to silicon are
drawn for
reasons of clarity. Specific non-limiting examples of cyclic arninosilicon
compounds
2o include:
H H
Z S/N H/J Z~ Z~S~N
Z~/ O Y, Z~/ ~O
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Jyo
J
z2~ o
J
Z'
Z
.1~
Z3 Z2
J N J Nw ~ J N N J2 /
s;,z4 ~ \ ~ ~ ~z3 z,
z1/s~ Z~~s~ s~~z
4
In these structures, each Z is independently one of H, X, R, OH, ORI, or
NJ1J2, with R
comprising at least one carbon atom, X being a halogen or a pseudohalogen, Rl
comprising at least one carbon atom. Each J is independently H or comprises at
least one
of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom. Each Y
moiety
1o independently comprises at Ieast one atom (for example, hydrogen, a
halogen, a
pseudohalogen, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.).
In any of the above-described embodiments, any one, two, three, four, five, or
six
of ZI, Z2, Z3, Z4, Z5, and Z6 (where applicable) may each independently
comprise a
silicon atom. Thus, the compound may have at least two, at least three, at
least four, at
15 Ieast five, etc. silicon atoms within its structure. In one embodiment, the
compound is a
polymer. An example of a compound having two silicon atoms within its
structure is:
Z1 Z4
z6
Z ~s~~Y~s~~z5
where each of Zl, Z2, Z3, Z4, Z5, and Z6 independently is one of H, X, R, OH,
ORI, or
v'~ v2
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NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and J2 each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom.
In some cases, the compound may have a structure that allows, or can be
hydrolyzed under physiological conditions to form a structure that allows,
multiple
silicon hydroxide moieties to simultaneously interact with aluminum or another
metal
ion. Schematic non-limiting examples are illustrated below, where M indicates
the
position of a metal ion, and each R moiety in the illustrated structures
independently
to comprises at least one atom interconnecting the silicon atoms (for example,
an alkyl
moiety, an aryl moiety, a cyclic moiety, an amine, etc.). Zl and Z2 each
independently is
one of H, X, R, OH, ORI, or NJ1J2, with R comprising at least one carbon atom,
X being
a halogen or a pseudohalogen, Rl comprising at least one carbon atom, and Jl
and J2 each
independently being H, or comprising at least one of a carbon atom, a nitrogen
atom, an
oxygen atom, or a sulfur atom. In these non-limiting examples, the
(noncovalent)
interaction of Si0- with the metal ion is indicated by -- .
R R ~ SI
R~° ~ R~~
0 1
/SIB _ /Sid /SILO' aO~SI~ 1/Si\ I 'O/SI~Y4
Z~ O. .O- ZZ Z~ ~ ~ Z2 Z O. I
.,M,.
O__;;M; ,_O .M..
~Si~ ~.Si~ ~Si~
R~° ~ R~~ R~° ~~ R~~ R~° ~~ Rya
0 1 ~ 00 1 ~ 00 1
Z1/SI\ ~' ~ e~ ~SI~Y4 z1/SI\ ~' ~ ~ ~ ~SI~Y4 Z,~/S~\O. ~i i~ ~. ~ ~SI~Y4
O___', M;.,.O O~_ _~; M~,..O .. M;,,.O
2o Non-limiting examples of such structures include:
H\ %H H\ %H H\ %H H\ %H Y H\ %H
/Si Si Sid ~Si Sid
H \ %H H \ %H CI\ j I CI\ j I
~S'~Si~Sy ~S~~Si~Si~
HO OH CI CI
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Cl\ % 1 C\ j I H \ j H H \ /CI HO CI
/Si Si Sid /Si S \
In these structures, Y comprises at least one atom (for example, hydrogen, a
halogen, a
pseudohalogen, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.).
In certain cases, the compound is a polymer having a repeat unit comprising at
least one silicon atom. In some cases, the silicon may be functionalized as
described
above (e.g., the silicon atom of the repeat unit may be covalently bonded to
one or more
of H, X, R, OH, ORI, or NJ1J2, with R comprising at least one carbon atom, X
being a
halogen or a pseudohalogen, Rl comprising at least one carbon atom, and Jl and
JZ each
to independently being H, or comprising at least one of a carbon atom, a
nitrogen atom, an
oxygen atom, or a sulfur atom). For example, in one embodiment, the compound
is a
polymer comprising a repeat unit having silanol, silandiol, or silantriol
functionality, or
the polymer comprises a repeat unit that can by hydrolyzed to form silanol,
silandiol, or
silantriol functionality. Non-limiting examples include:
OH OH OH OH Y
~Si (\Si
15 n n m
OH OR
CI\ % I LSi CI OH
/n\ (\Si
/n Y ~ n
% H O \ % H CI CI
~5i ('Si
.-~ n ~ n m
2o In these structures, Y comprises at least one atom (for example, hydrogen,
a halogen, a
pseudohalogen, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.), R
comprises at
Least one carbon atom, and n and m are positive integers. If the polymer is a
copolymer
(e.g., as shown above), the copolymer may be, for example, a block copolymer,
a
random copolymer, an alternating copolymer, a graft copolymer, etc.
25 In one set of embodiments, a compound of the invention is a cyclic
organosilicon
compound having at least one ester moiety, or a salt thereof. Non-limiting
examples of
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such compounds include:
1
O Z1
Z ~ i~I 2 S/O\A Z-S~ /A I \Si~
ZZ A Z ~O~ O A1 ~ ~A2
O O O O
O\S /O\A2 Si ~O~A I \S O \A3 A1/ \S'~ \pz
1~ ~O~ ~O/ A2~
In these structures, each A independently is a moiety having at least one of a
carbon
atom and a silicon atom, and each Z independently is one of H, X, R, OH, ORI,
or NJ1J2,
with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, Rl
comprising at least one carbon atom, and JI and JZ each independently being H,
or
comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or
a sulfur
atom. In some cases, each A may be chosen to render the compound more
hydrophobic
to or less hydrophobic, and/or to facilitate passage of the compound across
the blood-brain
barrier. Non-limiting examples of cyclic organosilicon esters of the invention
include:
O-Sip ~ O Si\O~ O~Si~O O/Si\O
O~Si\O~ O/Si\O O~Si~O O~ ~O
S~ S~ Si
O O O~ O
Z1 jS~
Z2 O Z2 O ~ Z2 O
In the above structures, Z1 and ZZ is each independently one of H, X, R, OH,
OR1, or
NJ'J2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, RI comprising at least one carbon atom, and Jl and JZ each
independently
being H, or comprising at least one of a carbon atom, a nitrogen atom, an
oxygen atom,
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or a sulfur atom. In the above structures, not all of the atoms bonded to
silicon are
drawn for reasons of clarity.
In another example, the compound has a structure:
to
11
where each of Al, A2, A3, A4, A5, A6, A', A8, A9, Al°, An, and A12
independently is H or
comprises at Ieast one carbon atom. Not all of the atoms bonded to silicon are
drawn for
reasons of clarity. In some cases, each of the A's may be chosen such that two
A
moieties joined by a common carbon atom of an oxasilinane ring are the same.
In certain
cases, each of the A's may be chosen such that the compound is symmetrical or
to nonchiral, or such that the compound is asymmetrical or chiral. In one
embodiment,
each A is either H or an alkyl moiety, such as methyl, ethyl, propyl, etc.
As previously discussed, the compound may have more than one silicon atom in
some embodiments. Additional non-limiting examples include:
0 /0 0
Z SI SI~Z4 ~/S~ SI~ 4
1$
Z3
Z \ ~ O~S Za
Si
O
O
In these structures, each of Zl, Z2, Z3, Z4, Z5, and Z6 is independently one
of H, X, R,
OH, ORI, or NJ1J2, with R comprising at least one carbon atom, X being a
halogen or a
pseudohalogen, Rl comprising at least one carbon atom, and Jl and J2 each
independently
2o being H, or comprising at Ieast one of a carbon atom, a nitrogen atom, an
oxygen atom,
or a sulfur atom.
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In yet another aspect, a compound of the invention may have a portion that
becomes positively charged (represented schematically herein by the symbol ~)
under
physiological conditions within the body, which may thereby cause the molecule
to
become less charged or zwitterionic in some cases (i.e., the molecule has a
positively
charged portion and a negatively charged portion, or the molecule has a net
dipole
moment). A Iess charged compound may facilitate transport of the compound into
the
brain in some cases, for example, across the blood-brain barrier or across a
cell
membrane. For instance, the compound may be represented by:
z~ z'
Z3
SI SI/
G ~~2 CG ~~2
or ,
1o where each of Z1 and ZZ independently is one of H, X, R, OH, OR1, or NJ1J2,
with R
comprising at least one carbon atom, X being a halogen or a pseudohalogen, Rl
comprising at least one carbon atom, and Jl and J2 each independently being H,
or
comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or
a sulfur
atom. In some cases, the compound may be present as a salt.
In one set of embodiments, ~ is an amine moiety. For example, the nitrogen
atom of the amine moiety may be located on one portion of the compound, which
may
give that portion of the compound a positive charge when exposed to certain
physiological solutions or conditions. Examples of suitable amines include
those
described above. The amine may be a primary amine, a secondary amine, a
tertiary
2o amine, or a quaternary amine. Fox example, if the amine is a tertiary
amine, the amine
may be a dimethylamine, an ethylmethylamine, a propylmethylamine, a
diethylamine,
etc. Specific non-limiting examples include a
bis(diallcylaminoallcyl)silandiol, a
bis(triallcylaminoallcyl)silandiol, or a tris(triallcylaminoallcyl)silantriol.
If more than one
amine moiety is present within the compound, the amines may each be the same
or
different. Other moieties that can provide positive charge (e.g., under
physiological
conditions) include, for example, amidines, guanidines, aryl amines,
heteroaryl amines,
pyridines, imidazoles, etc. Combinations of one or more moieties that can be
positively
charged under physiological conditions within a compound of the invention are
also
envisioned, for example, a compound having an amine moiety and a guanidine
moiety, a
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guanidine moiety and a pyridine, etc. Of course, when the molecule is charged,
one or
more counterions may also be present or associated with the compound, for
example, an
organic or an inorganic anion, such as chloride, fluoride, bromide, sulfate,
carbonate,
acetate, etc. if the compound is positively charged. Specific non-limiting
examples of
such compounds include:
\ /
N~ N~ \
/N~Si~ OH ~N~Si~
OH OH
\N/
N~
OH
~N~Si
N
N~
.J
In another aspect, the compound may have a structure that facilitates
transport of
the compound into an organ or across the blood-brain barrier. In one set of
embodiments, the compound may be designed so as to optimize the hydrophobicity
of
the composition to facilitate transpou of the compound into the organ or
across the
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blood-brain barrier (e.g., via diffusion, or using a transport system such as
transport
proteins or ion channels). In some cases, the compound's ability to move into
the organ
or across the blood-brain barrier may be lost when the compound binds to a
metal ion
such as aluminum, or when the compound enters the brain or other organ, or in
transit
(i.e., within the cells that form the blood-brain barrier, etc). In other
cases, the
compound may retain or improve its ability to move into an organ or cross the
blood-
brain barrier when bound to a metal ion. In one set of embodiments, positive,
negative,
and/or hydrophobic moieties may be attached to the compound so as to achieve a
selected hydrophobicity and/or a selected electric dipole moment of the
compound. The
hydrophobicity of the compound may be determined by those of ordinary skill in
the art
using any suitable test, for example, by partitioning the compound in a two-
phase liquid
system, such as a water-octanol system, or other suitable systems known to
those of
ordinary skill in the art. For example, the hydrophobicity of a compound may
be
determined by allowing the compound to partition in a water-octanol system,
and
determining the percentage of the compound in the octanol phase relative to
the water
phase (e.g., on a per mass basis or other quantitative measurement). The water-
octanol
partition coefficient may be chosen such to optimize penetration of the blood-
brain
barrier in certain instances, and may depend on actual physiological
conditions. See,
e.g., Lohmann, et al., "Predicting Blood-Brain Barrier Permeability of Drugs:
Evaluation
of Different In Tliti°o Assays," J. Drug Targeting, 10(4): 263-276,
2002. In some cases,
the octanol/water partition ratio for a hydrophobic compound is at least about
1.25:1
(octanol:water), at least about 1.5:1, at least about 1.75:1, at least about
2: l, at least about
5:1, at least about 10:1, at least about 20:1, at least about 50:1, at least
about 100:1, at
least about 300:1, or at least about 1000:1 or greater. In some cases, a
hydrophobic
compound may more readily cross the blood-brain barrier or other similar
barrier or
membrane to enter into the brain or other organ. Thus, in one embodiment, the
compound includes one or more hydrophobic or lipophilic moieties, for example,
an
alkyl moiety, a cycloalkyl moiety, an aryl moiety, or the like.
In another set of embodiments, a compound of the invention includes a
chelating
3o agent able to bind to aluminum or another metal ion (or is able to form a
chelating agent
able to bond to aluminum or another metal ion). In one embodiment, a compound
of the
invention has a structure:
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X-'Y or X-Y
where X is a chelating agent able to bond to aluminum or another metal ion, or
is able to
form a chelating agent able to bond to aluminum or another metal ion.
Additionally, Y is
a structure able to facilitate transport of the compound (or a portion
thereof] across the
blood brain-barrier, the structure ~ comprises at least one chemical bond, and
the
structure - is a moiety that can be hydrolyzed under physiological conditions,
e.g.,
within the brain, the blood-brain barrier, or within the bloodstream. In some
cases, the
structure ~ includes at least one atom that connects structure X and structure
Y (e.g.,
the structure ~ may include two atoms bridging between X and Y, three atoms
1o bridging between X and Y, four atoms bridging between X and Y, five atoms
bridging
between X and Y, etc.). Suitable hydrolyzable structures interconnecting X and
Y
include, for example, alkoxide moieties, ester moieties, or ether moieties,
e.g., as
previously described. Other suitable hydrolyzable structures will be lalown to
those of
ordinary skill in the axt. In some cases, the hydrolyzable structures may be
chosen to
control the degradation rate of the compound within the brain (for example, if
the release
of Y activates X in the above structure). For example, a compound having a Si-
F bond
may hydrolyze at a relatively slow rate, while a compound having a Si-Cl or Si-
Br bond
may hydrolyze at a relatively faster rate. Slow rates of degradation may be
desirable in
some cases, for example, when slow or controlled release of the compound is
desired.
2o Different compounds having different halogens may also be administered
together to
provide short and long term activity in certain cases.
As an example, in one embodiment, Y is a targeting moiety able to target a
component of the blood-brain barrier to facilitate transport, such as via an
endogenous
transport pathway, for example, by mimicking proteins or other substrates
naturally
transported by the targeted endogenous transport protein. For example, the
composition
may be selected to mimic a substrate for a hexose transporter, a
monocarboxylate
transporter, an amino acid transporter, a glucose transporter, a peptide
transporter (for
example, transporters for enlcephalins, vasopressin, apamins, etc.), a protein
transporter
(e.g., transferrin), or the like. For example, a compound ofthe invention
targeted
3o towards transport across the blood-brain barrier using a carbohydrate
transporter may
have a structure such as:
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Z1 Z1 ,J1~ Z1 Z1
Zs' ~ I-I Zs' ~ Zs' I Z3
Z~Si~ /N~ ~,Si~ /N~
Z Y Cb Z Y Cb Z Y Z Cb
In these structures, each of ZI, Z2, and Z3 independently is one of H, X, R,
OH, OR1, or
NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, and Rl comprising at least one carbon atom. Each J
independently is H
or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom,
or a sulfur
atom, Y is an interconnecting moiety (for example, an alkyl moiety, an aryl
moiety, a
cyclic moiety, etc.), and Cb comprises a carbohydrate moiety (or a portion
thereof). In
some cases, Cb is an entity that substantially derives from a carbohydrate or
a portion
thereof. For example, a reaction of a carbohydrate with an aminosilicon
composition or
1o an amidated silicon compound may be used to produce a composition of the
compound.
In some cases, the carbohydrate may be an aldehyde sugar ("aldocarbose")
(e.g.,
aldohexose or aldopentose) or a ketone sugar ("ketocarbose") (e.g.,
lcetohexose or
ketopentose), or a moiety derived from an aldocarbose or a ketocarbose. For
example,
the carbohydrate may be amidated, aminated, esterified, etc. Other
carbohydrate
derivitization reactions will be Icnown to those of ordinary skill in the art.
In some cases,
at least a portion of the carbohydrate may be an aldehyde sugar or a lcetone
sugar.
As another example, the composition may have a structure such as:
Z1 Z1 .J1~ Z1 Z1
3\ Z3
Z jsi~ /N~ Z2rSi~ /N~ Z3 ~si~ r(Aa)n
Z Y (Aa)" Z Y (Aa)~ ZZ Y Z (Aa)~
In these structures, each of Zl, Z2, and Z3 independently is one of a H, X, R,
OH, ORI, or
2o NJ1J2, with R comprising at least one carbon atom, X being a halogen or a
pseudohalogen, and Rl comprising at least one carbon atom. Also, each J
independently
is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen
atom, or a
sulfur atom, Y is an interconnecting moiety (for example, an alkyl moiety, an
aryl
moiety, a cyclic moiety, etc.), and Aa comprises one or more amino acids
(i.e., n may be
1, 2, 3, a peptide, a protein, etc.) andlor one or more amino acid
derivatives. In some
cases, n may be a positive integer less than about 50, less than about 20, or
less than
about 10.
Such compounds may be prepared, for example, by reacting a suitable
aminosilicon compound with a carbohydrate, an amino acid, a peptide, a
protein, a
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hormone, a neurotransmitter, etc. using coupling reactions known to those to
ordinary
skill in the art.
In another set of embodiments, a compound of the invention may be packaged or
included in a virus, for example, a virus that is targeted towards the brain
or other organ.
For example, a virus may be loaded with a silanol, a silandiol, or a
silantriol, and/or a
compound able to form a silanol, a silandiol, or a silantriol upon hydrolysis
and/or
release from the virus. In some cases, the viruses may be prepared by
assembling the
viral envelope of the virus in the presence of one or more compounds of the
invention,
thus facilitating internal loading of the virus with the compounds of the
invention.
to In yet another aspect, the compound may have a detectable moiety, i.e., a
moiety
that facilitates external detection, e.g., in vivo or in vitro. For example, a
portion of the
compound may be radioactively and/or fluorescently labeled. Such compounds can
be
prepared using coupling reactions known to those of ordinary skill in the art.
As an
example, a compound having a structure:
~1 Z1
/NJ1J~ Z jSi~ 1 z
15 Z Y or ZZ NJ J
may be reacted with an acyl, isocyanate, or an isothiocyanate moiety on, or
attached to, a
fluorescent moiety, thereby producing a detectable compound. As another
example, a
compound having a structure:
~1 ~1 Z1 Z1
Z3 j ~I~ /NCO z3 jSl~ /NCS z3 j ~I~ Z3 jSl~
ZZ Y , ZZ Y , ZZ NCO, or ZZ NCS
2o may be reacted with an NH2, a SH, or an OH moiety on, or attached to, a
fluorescent
moiety to produce a detectable compound. In the above structures, each Z is
independently one of H, X, R, OH, ORI, or NJIJz, with R comprising at least
one carbon
atom, X being a halogen or a pseudohalogen, Rl comprising at least one carbon
atom,
and Jl and J2 each independently being H, or comprising at least one of a
carbon atom, a
25 nitrogen atom, an oxygen atom, or a sulfur atom. Y is a moiety
interconnecting Si and N
(for example, an alleyl moiety, an aryl moiety, a cyclic moiety, etc.). Those
of ordinary
skill in the art will know of suitable fluorescent labels for use in the above
structures. As
one particular example, the fluorescent label may be FITC or a FITC
derivative,
fluorescein, GFP, etc.
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The detectable moiety, in another set of embodiments, includes a radioactive
atom, for example, 3H, 14C, 33P~ 32P~ lash i3ih sss~ etc. Those of ordinary
slcill in the art
will know of suitable ways to incorporate a radioactive Iabel into a compound
of the
invention. As one particular example, if the detectable moiety is tritium (3H
or T),
tritium can be incorporated into the compound using a reducing reaction. For
example, a
tritiated lithium aluminum hydride (e.g., LiAlT4, LiAIHTs, LiAIHZT2, and/or
LiAIH3T)
may be reacted with a functional moiety, resulting in reduction of the
functional moiety
and incorporation of a tritium label into the compound. Non-limiting examples
of useful
reducing reactions include:
T~
R-CN --~ R-C-NH2
O
Tz
R-C-OH --~ R-C-OH
OH
O
R~- ~ -Rz
R~- IC-Rz ~ T
H
R-N=C=O -> R-N-CT3
O
R~ N- ~ ~ -Rz ~ R~-N C Rz
O
HO
R O
R CTz
j H
O --~ CT2
O ,.OH
R~ ---~~R
CH2T
In the above structures, each R (or, for structures with Rl and R2, at least
one of Rl and
R2) comprises at least one silicon atom. It should be understood that, for any
T in the
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above structure, the actual reaction products will include a mixture of
labeled (tritiated)
and unlabeled hydrogen atoms.
In one aspect of the invention, the compositions of the invention may be
assayed
for transport across subject cells. In one set of embodiments, the cells are
cells that can
be used to model the blood-brain barrier, for example, Caco-2 cells or bMVEC
cells
("bovine microvascular epithelial cells"). For example, transport of a
composition of the
invention across a monolayer of the cells may be used to determine or predict
the
transport or uptake rate of the composition (or a portion thereof) across the
blood-brain
barrier. Transport of the composition may be determined, for example, using CD
or
to similar techniques, such as atomic absorption, spectroscopy, mass
spectroscopy,
radioactive tracer measurements, or the like. In some cases, a composition of
the
invention may be determined by its transport behavior across a monolayer of
cells, i.e., a
composition of the invention may be transpoued across the cell monolayer at a
substantial rate. Thus, a composition "able to cross" the blood-brain barrier
(or other
15 membrane) may be determined, in some cases, by the compound's ability to
cross a
monolayer of cells, such as Caco-2 cells or bMVEC cells. Other examples of
suitable
cell models are described in Lohmann, et al., "Predicting Blood-Brain Barrier
Permeability of Drugs: Evaluation of Different Ih Vitro Assays," J. Drug
Ta~~getifzg,
10(4): 263-276, 2002.
2o In another set of embodiments, the toxicity of a test compound against
cells such
as human cells is determined. A step of selecting test compounds that are
substantially
non-toxic to subject cells is provided. "Substantially non-toxic," as used
herein means
that the test compound can be administered to a subject with an acceptable
amount of
damage (preferably, no detectable damage) to the subject cells. The damage to
the cells
25 may be indicated by altered cell metabolism, cell morphology, cell mitosis,
necrosis,
apoptosis, etc. An acceptable amount of damage can be determined by one of
skill in the
art with no more than routine experimentation. Acceptable amounts of damage
may
depend on route of administration, risk of side effects versus benefit of
administration,
etc.
3o In another aspect, the compositions and methods of the invention may be
used in
diagnostic or assay techniques. For example, a composition of the invention
may be
used in an assay such as an aluminum detection assay or a metal ion detection
assay. A
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sample having a known or unknown concentration of aluminum or other metal ion
may
be added to a solution containing a composition of the invention, and the
amount or
degree of binding of the composition (or a portion thereof) to the aluminum or
other
metal ion may be determined, using techniques known by those of ordinary skill
in the
s art, fox example, using circular dichroism or mass spectroscopy. As another
example,
the invention may be used in a cell culture system, for example, in a cell
culture that
includes neural and/or other types of cells, such as a cell able to produce
beta-amyloid
and/or a neurofilament protein. In one set of embodiments, a composition of
the
invention is added to a cell culture, optionally with a known or unknown
concentration
to of aluminum or other metal ion, and the net effect on cell function of the
combination of
the aluminum or other metal ion and the organosilicon composition of the
invention is
determined using techniques known to those of ordinary skill in the art. In
another set of
embodiments, a cell culture is used to detect and/or determine the
concentration of
aluminum (or other metal ion) in a sample using the methods and compositions
of the
15 invention, which may be a sample of biological origin in some cases. In one
embodiment, a cell culture, a diagnostic, or an assay may be used to determine
proper
dosing to achieve a certain specified result (e.g., a certain concentration of
free aluminum
ions) when the composition is applied to a subject.
Another aspect of the invention provides a method of administering a
2o composition of the invention to a subject. When administered, the
compositions of the
invention are applied in a therapeutically effective, pharmaceutically
acceptable amount
as a pharmaceutically acceptable formulation. As used herein, the term
"pharmaceutically acceptable" is given its ordinary meaning as used in the
art.
Pharmaceutically acceptable compounds are generally compatible with other
materials of
25 the formulation and are not generally deleterious to the subject. A
composition of the
invention (or prodrug form of the composition) may be administered to the
subject in any
therapeutically effective dose or treatment. A "therapeutically effective"
dose or amount
is capable of at least partially preventing or reversing symptoms related to
the adverse
effects of metal ions as previously discussed, for example, neurofibrillary
tangles or
3o senile plaque formation in the brain. A therapeutically effective amount
may be
determined by those of ordinary skill in the art, for instance, employing
factors such as
those further described below and using no more than routine experimentation.
In one
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embodiment, the subject being so treated is not indicated as having a disease
or condition
treatable by the inhibition of leukocyte elastase.
In administering the compositions of the invention to a subj ect, dosing
amounts,
dosing schedules, routes of administration, and the like may be selected so as
to affect
known activities of the compositions of the invention. Dosages may be
estimated based
on the results of experimental models, optionally in combination with the
results of
assays of compositions of the present invention. Dosage may be adjusted
appropriately
to achieve desired drug levels, local or systemic, depending upon the mode of
administration. The doses may be given in one or several administrations per
day. In
1o some cases, parenteral administration of the composition may be from one to
several
orders of magnitude lower dose per day, as compared to oral doses. In the
event that the
response of a particular subject is insufficient at such doses, even higher
doses (or
effectively higher doses by a different, more localized delivery route) may be
employed
to the extent that subject tolerance permits. Multiple doses per day are also
contemplated, in certain cases, to achieve appropriate levels of the
composition within
the subject or within the active site of the subject, such as within the
brain.
The dose of the composition to the subject may be such that a therapeutically
effective amount of the composition (or a portion thereof, such as an
organosilicon
compound) reaches or enters the brain or other active site. The dosage may be
given in
2o some cases at the maximum amount while avoiding or minimizing any
potentially
detrimental side effects to the subject. For example, the dose of the
organosilicon
composition may be about 0.1 mcmol/lcg ("micromoles"/lcg) to about 50
mcmol/kg, or
about 0.5 mcmol/kg to about 5.0 mcmol/kg. The dosage of the composition that
is
actually administered is dependent upon factors such as the final
concentration desired at
the active site, the method of administration to the subject, the efficacy of
the
composition, the longevity (i.e., half life) within the subject of the
composition, the
timing of administration relative to the formation of the tangles and/or
plaques the
frequency of treatment, the effect of concurrent treatments, etc. The dose
delivered may
also depend on conditions associated with the subject, and can vary from
subject to
subject in some cases. For example, the age, sex, weight, size, environment,
physical
conditions, or current state of health of the subject may also influence the
dose required
andlor the concentration of the composition (or portion thereof) at the active
site.
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Variations in dosing may occur between different individuals or even within
the same
individual on different days. It may be preferred that a maximum dose be used,
that is,
the highest safe dose according to sound medical judgment. Preferably, the
dosage form
is such that it does not substantially deleteriously affect the subject. The
specific
dosages) given to the subject can thus be determined by those of ordinary
skill in the art,
using no more than routine experimentation.
Administration of the compositions of the invention may be accomplished by any
medically acceptable method which allows the composition (or portion thereof)
to reach
its target. The particular mode selected will depend, of course, upon factors
such as the
to particular composition, the severity of the state of the subject being
treated, or the dosage
required for therapeutic efficacy. As used herein, a "medically acceptable"
mode of
treatment is a mode able to produce effective levels of the composition (or
portion
thereof) within the subject, without causing clinically unacceptable adverse
effects. A
"target" or "active site" is the location where a composition (or portion
thereof) of the
invention is able to bind to a metal ion and/or inhibit interaction between
the metal ion
and components of the body adversely affected by the presence of the metal
ion, such as
with beta-amyloid or neurofilament proteins. The inhibition of the metal ion
may occur
before or after the metal ion complexes or otherwise inactivates such
components
adversely affected. Non-limiting examples of such targets include the
bloodstream or the
brain.
Airy medically acceptable method may be used to administer the composition to
the subject. The administration may be localized (i.e., to a particular
region,
physiological system, tissue, organ, or cell type) or systemic, depending on
the condition
to be treated. For example, the composition may be administered orally,
vaginally,
rectally, buccally, pulmonary, topically, nasally, transdermally through
parenteral
injection or implantation, via surgical administration, or any other method of
administration where access to the target by the composition of the invention
is achieved.
As another example, any of the compositions described herein may be injected
directly
into the brain, spinal cord, or other organ, or the composition may be
injected in a region
3o such that it will be transported into the brain, spinal cord, or other
organ, for example,
injected into the cerebrospinal fluid. Examples of parenteral modalities that
can be used
with the invention include intravenous, intradermal, subcutaneous,
intracavity,
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intramuscular, intraperitoneal, epidural, or intrathecal. Examples of
implantation
modalities include any implantable or injectable drug delivery system. In one
embodiment, the implantable delivery system is a subdural article containing
the
organosilicon composition, placed in direct contact with the brain, for
example, through
surgery. The article may have any suitable form for implantation within the
brain, fox
example, a sponge, a film, a blanket, a pad, a wafer, a disc, etc. In certain
cases, the
article may be removed (and optionally replaced with a new article) after a
suitable
period of time has passed, for example, after a fixed time, such as a day, a
week, or a
month. In certain instances, the article may be removed when a certain
condition is
1o reached, for example, once a certain amount or percentage of the
composition has
diffused out of the article and/or when a certain amount of aluminum has been
bound to
the article. In other cases, the article may be allowed to remain within the
subject
indefinitely. For example, a sponge may include one or more compositions of
the
invention, which may be released from the sponge upon implantation, or which
may
remain mobilized within the sponge.
Oral administration may be preferred in some embodiments because of the
convenience to the subject as well as the dosing schedule. Compositions
suitable for oral
administration may be presented as discrete units such as hard or soft
capsules, pills,
cachettes, tablets, troches, or lozenges, each containing a predetermined
amount of the
2o active compound of the composition. Other oral compositions suitable for
use with the
invention include solutions or suspensions in aqueous or non-aqueous liquids
such as a
syrup, an elixir, or an emulsion. In another set of embodiments, the
composition may be
used to fortify a food or a beverage.
In certain embodiments of the invention, the administration of the composition
of
the invention may be designed so as to result in sequential exposures to the
composition
over a certain time period, for example, hours, days, weeks, months or years.
This may
be accomplished by repeated administrations of the composition by one of the
methods
described above, or by a sustained or controlled release delivery system in
which the
composition is delivered over a prolonged period without repeated
administrations.
3o Administration of the composition using such a delivery system may be, for
example, by
oral dosage forms, bolus injections, transdermal patches or subcutaneous
implants.
Maintaining a substantially constant concentration of the composition may be
preferred
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in some cases, for example, to allow fox scavenging of metal ions such as
aluminum
throughout the body, and promoting excretion of the metal ions via the kidney
and
bowel, or to allow for reaction with components of the body adversely affected
by the
metal ions, such as neurofibrillary tangles or senile plaque. However,
avoidance of short-
term elevated levels of compositions within the body may be desired in some
cases, for
instance, to minimize the precipitation of silicate kidney stones in the
presence of non-
physiological levels of silicon and silicon-containing compounds.
Other delivery systems suitable for use with the present invention (e.g.,
where
alteration and/or control of the release kinetics is desired) include time-
release, delayed
1o release, sustained release, or controlled release delivery systems. Such
systems may
avoid repeated administrations of the composition in many cases, increasing
convenience
to the subject. Many types of release delivery systems are available and known
to those
of ordinary skill in the art. They include, for example, polymer-based systems
such as
polylactic and/or polyglycolic acids, polyanhydrides, polycaprolactones and/or
15 combinations of these; nonpolymer systems that are lipid-based including
sterols such as
cholesterol, cholesterol esters, and fatty acids or neutral fats such as mono-
, di- and
triglycerides; hydrogel release systems; liposome-based systems; phospholipid
based-
systems; silastic systems; peptide based systems; wax coatings; compressed
tablets using
conventional binders and excipients; or partially fused implants. Specific
examples
2o include, but are not limited to, erosional systems in which the composition
is contained
in a form within a matrix (for example, as described in U.S. Patent Nos.
4,452,775,
4,675,189, and 5,736,152), or diffusional systems in which an active component
controls
the release rate (for example, as described in U.S. Patent Nos. 3,854,480,
5,133,974 and
5,407,686). The formulation may be as, for example, microspheres, hydrogels,
25 polymeric reservoirs, cholesterol matrices, or polymeric systems. In some
embodiments,
the system may allow sustained or controlled release of the composition to
occur, for
example, through control of the diffusion or erosion/degradation rate of the
formulation
containing the composition. In addition, a pump-based hardware delivery system
may be
used to deliver one or more embodiments of the invention.
3o Use of a long-term release implant may be particularly suitable in some
embodiments of the invention. "Long-term release," as used herein, means that
the
. implant containing the composition is constructed and arranged to deliver
therapeutically
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effective levels of the composition for at least 30 or 45 days, and preferably
at least 60 or
90 days, or even longer in some cases. Long-term release implants are well
known to
those of ordinary skill in the art, and include some of the release systems
described
above.
In certain embodiments of the invention, the composition of the invention is
administered to subjects who have a family history of Alzheimer's disease or
other
disease that is characterized by an excess of metal ions, or to subjects who
have a genetic
predisposition for the disease. In other embodiments, the composition is
administered to
subjects who have reached a particular age, or to subjects more likely to get
the disease.
1o In yet other embodiments, the composition may be administered to subjects
who exhibit
symptoms of the disease (e.g., early or advanced). In still other embodiments,
the
composition may be administered to subjects as a preventive measure. In some
embodiments, the composition is administered to subjects based on demographics
or
epidemiological studies, for example, to persons living in a certain
geographic area, such
15 as areas where a high concentration of metal ions such as aluminum axe
present in the
groundwater; or to persons in a particular field, for example, workers in the
aluminum or
lead industry, or workers who use aluminum compounds or materials.
Alzheimer's disease may be characterized in a subject by those of ordinary
skill
in the art prior to treatment with the compositions of the invention. For
example, a
2o biological sample for the subject such as a blood test, a urine test, a
biopsy, a spinal tap,
etc., may be analyzed using an appropriate analytical technique and a
concentration of
ions (e.g. metal ions such as aluminum) may be determined and compared to
normal
values. For example, an ion concentration may be determined by NMR, mass
spectrometry, ICP, emission spectroscopy, fluorescence spectrometry, ELISA, a
25 chemical stain or indicator, etc. As another example, a subject may be
directly tested to
determine if a disease exists or may exist (i.e., the subject is susceptible
to the disease),
for example, using MRI, CAT scans, X-rays, etc. In another set of embodiments,
a
subject may be diagnosed as having or being at risk for Alzheimer's disease by
a medical
professional using routine practice. Alzheimer's disease may be diagnosed, for
example,
3o by considering the medical history, including such information as the
person's general
health, past medical problems, andlor any difficulties the subject has in
performing
carrying out daily activities; medical tests such as tests of blood, urine, or
spinal fluid;
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neuropsychological tests such as memory, problem solving, attention, counting,
and
language tests; andlor brain scans, for example, using electroencephalograms,
MRI,
CAT, or PET scans; and behavioral indicators such as memory loss, personality
change,
dementia, speech problems, cognitive or reasoning problems, eating problems,
incontinence, motor control problems, etc. Research studies have also
indicated a
general decrease in cerebrospinal fluid (CSF) beta-amyloid levels with an
increase in tau
protein may be indicative of a subject having or at risk for disease.l An
improvement or
arresting of at least some of the above indications may be related to the
effectiveness of
the inventive compositions. Of course, effectiveness may be measured by any of
the
to techniques known to those skilled in the art, including, but not limited
to, those listed
above.
Administration of the compositions of the invention (or prodrug form of the
composition) can be alone, or in combination with other therapeutic agents
and/or
compositions (e.g., other agents or compositions that can be used to treat
Alzheimer's
15 disease or other disease that is characterized by an excess of metal ions).
In certain
embodiments, the compositions of the invention can be combined with a suitable
pharmaceutically acceptable carrier, for example, as incorporated into a
liposome,
incorporated into a polymer release system, or suspended in a liquid, e.g., in
a dissolved
form or a colloidal form. The carrier may be either soluble or insoluble,
depending on
2o the application. Compositions of the invention that may be pharmaceutically
acceptable
include not only the active compound, but also formulation ingredients such as
salts,
carriers, buffering agents, emulsifiers, diluents, excipients, chelating
agents, drying
agents, antioxidants, antimicrobials, preservatives, binding agents, bullring
agents,
solubilizers, or stabilizers that may be used with the active compound. For
example, if
25 the formulation is a liquid, the carrier may be a solvent, partial solvent,
or non-solvent,
and may be aqueous or organically based. Examples of suitable formulation
ingredients
include diluents such as calcium carbonate, sodium carbonate, lactose, kaolin,
calcium
phosphate, or sodium phosphate; granulating and disintegrating agents such as
corn
starch or algenic acid; binding agents such as starch, gelatin or acacia;
lubricating agents
3o such as magnesium stearate, stearic acid, or talc; time-delay materials
such as glycerol
~ Harrison's Principles of Internal Medicine, 15t~' Edition, CD-ROM, McGraw-
Hill, 2001
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monostearate or glycerol distearate; suspending agents such as sodium
carboxymethylcellulose, methylcellulose, hydroxypropyhnethylcellulose, sodium
alginate, polyvinylpyrrolidone; dispersing or wetting agents such as lecithin
or other
naturally-occurring phosphatides; thickening agents such as cetyl alcohol or
beeswax;
buffering agents such as acetic acid and salts thereof, citric acid and salts
thereof, boric
acid and salts thereof, or phosphoric acid and salts thereof; or preservatives
such as
benzalkonium chloride, chlorobutanol, parabens, or thimerosal. Suitable
carrier
concentrations can be determined by those of ordinary skill in the art, using
no more than
routine experimentation. The compositions of the invention may be formulated
into
1o preparations in solid, semi-solid, liquid or gaseous forms such as tablets,
capsules,
elixirs, powders, granules, ointments, solutions, depositories, inhalants or
injectables.
Those of ordinary skill in the art will know of other suitable formulation
ingredients, or
will be able to ascertain such, using only routine experimentation.
In general, pharmaceutically acceptable carriers suitable for use in the
invention
15 are well-known to those of ordinary skill in the art. As used herein, a
"pharmaceutically
acceptable carrier" refers to a non-toxic material that does not significantly
interfere with
the effectiveness of the biological activity of the active compounds) to be
administered,
but is used as a formulation ingredient, for example, to stabilize or protect
the active
compounds) within the composition before use. The term "carrier" denotes an
organic
20 or inorganic ingredient, which may be natural or synthetic, with which one
or more
active compounds of the invention are combined to facilitate the application
of the
composition. The carrier may be co-mingled or otherwise mixed with one or more
active
compounds of the present invention, and with each other, in a manner such that
there is
no interaction which would substantially impair the desired pharmaceutical
efficacy.
25 Pharmaceutically acceptable carriers include, for example, diluents,
emulsifiers, fillers,
salts, buffers, excipients, drying agents, antioxidants, preservatives,
binding agents,
bullring agents, chelating agents, stabilizers, solubilizers, silicas, and
other materials
well-known in the art.
Preparations include sterile aqueous or nonaqueous solutions, suspensions and
3o emulsions, which can be isotonic with the blood of the subject in certain
embodiments.
Examples of nonaqueous solvents are polypropylene glycol, polyethylene glycol,
vegetable oil such as olive oil, sesame oil, coconut oil, peanut oil,
injectable organic
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esters such as ethyl oleate, or fixed oils including synthetic mono or di-
glycerides.
Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or
suspensions,
including saline and buffered media. Parenteral vehicles include sodium
chloride
solution, 1,3-butandiol, Ringer's dextrose, dextrose and sodium chloride,
lactated
Ringer's or fixed oils. Intravenous vehicles include fluid and nutrient
replenishers,
electrolyte replenishers (such as those based on Ringer's dextrose), and the
like.
Preservatives and/or other additives may also be present such as, for example,
antimicrobials, antioxidants, chelating agents and inert gases and the like.
Those of skill
in the art can readily determine the various parameters for preparing and
formulating the
to compositions of the invention without resort to undue experimentation.
In some embodiments, the present invention includes a step of bringing a
composition or compound of the invention into association or contact with a
suitable
carrier, which may constitute one or more accessory ingredients. The final
compositions
may be prepared by any suitable technique, for example, by uniformly and
intimately
15 bringing the composition into association with a liquid carrier, a finely
divided solid
carrier or both, optionally with one or more formulation ingredients as
previously
described, and then, if necessary, shaping the product.
In some embodiments, a compound of the present invention may be present as a
pharmaceutically acceptable salt. The term."pharmaceutically acceptable salts"
includes
2o salts of the compound, prepared in combination with, for example, acids or
bases,
depending on the particular compounds found within the composition and the
treatment
modality desired. Pharmaceutically acceptable salts can be prepared as
alkaline metal
salts, such as lithium, sodium, or potassimn salts; or as alkaline earth
salts, such as
beryllium, magnesium or calcium salts. Examples of suitable bases that may be
used to
25 form salts include ammonium, or mineral bases such as sodium hydroxide,
lithium
hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and
the Iike.
Examples of suitable acids that may be used to form salts include inorganic or
mineral
acids such as hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric,
carbonic,
monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric,
3o sulfuric, monohydrogensulfuric, phosphorous acids and the like. Other
suitable acids
include organic acids, for example, acetic, propionic, isobutyric, malefic,
malonic,
benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-
tolylsulfonic,
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citric, tartaric, methanesulfonic, glucuronic, galacturonic, salicylic,
formic, naphthalene-
2-sulfonic, and the like. Still other suitable acids include amino acids such
as arginate,
aspartate, glutamate, and the like.
In one aspect of the invention, the composition comprises homologs, analogs,
derivatives, enantiomers and/or functionally equivalent compositions thereof
of the
compounds of the invention, such as any of the above-described compounds. Such
homologs, analogs, derivatives, enantiomers and functionally equivalent
compositions
thereof of the compounds may be used in any of the assays, methods, or
compositions
described above that are able to detect or treat Alzheimer's disease or other
diseases
to characterized by the presence of metal ions. "Functionally equivalent"
generally refers
to a composition capable of treatment of a subject that exhibits symptoms of
Alzheimer's
disease or other diseases characterized by the presence of metal ions, a
subject
susceptible to or otherwise at increased risk for such diseases, or a subject
not exhibiting
symptoms of such diseases, but for whom it is desired to decrease the risk of
such
15 diseases (e.g., a vaccination or a prophylactic treatment). It will be
understood one of
ordinary skill in the art will be able to manipulate the conditions in a
manner to prepare
such homologs, analogs, derivatives, enantiomers and functionally equivalent
compositions. Thus, homologs, analogs, derivatives, enantiomers and/or
functionally
equivalent compositions which are about as effective or more effective than
the parent
2o compound are also intended for use in the methods of the invention.
Synthesis of such
compositions may be accomplished through typical chemical modification methods
such
as those routinely practiced in the art.
Another aspect of the present invention involves a method comprising providing
any of the compositions of the present invention (or portions thereof), and
performing a
25 combinatorial synthesis on the composition, preferably to obtain homologs,
analogs,
derivatives, enantiomers and functionally equivalent compositions thereof of
the
composition. An assay may be performed with the homolog, analog, derivative,
enantiomer or functionally equivalent composition to determine its
effectiveness in
treating, preventing, or inhibiting Alzheimer's disease or other diseases
characterized by
3o the presence of metal ions. The combinatorial synthesis can involve
subjecting a
plurality of the compositions described herein to combinatorial synthesis,
using
techniques known to those of ordinary skill in the art.
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The present invention also provides any of the above-mentioned compositions
useful for the treatment of Alzheimer's disease or other diseases
characterized by the
presence of metal ions packaged in kits, optionally including instructions fox
use of the
composition for the treatment of such diseases. That is, the kit can include a
description
of use of the composition for participation in any biological or chemical
mechanism
disclosed herein associated with Alzheimer's disease or other diseases
characterized by
the presence of metal ions. The lcit can include a description of use of the
compositions
as discussed herein. The kit also can include instructions for use of a
combination of two
or more compositions of the invention. Instructions also may be provided for
l0 administering the drug by any suitable technique, as described above.
The invention also involves, in some embodiments, the promotion of the
treatment of Alzheimer's disease or other diseases characterized by the
presence of metal
ions according to any of the techniques and compositions described herein. As
used
herein, "promoted" includes all methods of doing business including, but not
limited to,
15 methods of selling, advertising, assigning, licensing, contracting,
instructing, educating,
researching, importing, exporting, negotiating, financing, loaning, trading,
vending,
reselling, distributing, replacing, or the like that can be associated with
the methods and
compositions of the invention, e.g., as discussed herein. Promoting may also
include, in
some cases, seeking approval from a government agency to sell a composition of
the
2o invention for medicinal purposes. Methods of promotion can be performed by
any party
including, but not limited to, businesses (public or private), contractual or
sub-
contractual agencies, educational institutions such as colleges and
universities, research
institutions, hospitals or other clinical institutions, governmental agencies,
etc.
Promotional activities may include instructions or communications of any form
(e.g.,
25 written, oral, and/or electronic communications, such as, but not limited
to, e-mail,
telephonic, facsimile, Internet, Web-based, etc.) that are clearly associated
with the
invention. As used herein, "instructions" can define a component of
instructional utility
(e.g., directions, guides, warnings, labels, notes, FAQs ("frequently asleed
questions"),
etc., and typically involve written instructions on or associated with the
composition
30 and/or with the packaging of the composition, for example, use or
administration of the
composition, e.g., in the treatment or prevention of Alzheimer's disease or
other diseases
characterized by the presence of metal ions. Instructions can also include
instructional
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communications in any form (e.g., oral, electronic, digital, optical, visual,
etc.), pt~ed
in any manner such that a user will clearly recognize that the instructions
are to be
associated with the composition, e.g., as discussed herein.
A "kit," as used herein, defines a package including any one or a combination
of
the compositions of the invention, and/or homologs, analogs, derivatives,
enantiomers
and functionally equivalent compositions thereof, and the instructions, but
can also
include the composition of the invention and instructions of any form that are
provided
in connection with the composition in a manner such that a clinical
professional will
clearly recognize that the instructions are to be associated with the specific
composition,
to for example, as described above. The kits described herein may also
contain, in some
cases, one or more containers, which can contain compositions such as those
described
above. The kits also may contain instructions for mixing, diluting, and/or
administrating
the composition. The kits also can include other containers with one or more
solvents,
surfactants, preservative and/or diluents (e.g., normal saline (0.9% NaCI), or
5%
dextrose) as well as containers for mixing, diluting or administering the
composition to
the subject.
The compositions of the kit may be provided as any suitable form, for example,
as liquid solutions or as dried powders. When the composition provided is a
dry powder,
the composition may be reconstituted by the addition of a suitable solvent,
which may
2o also be provided. In embodiments where liquid forms of the composition are
used, the
liquid form may be concentrated or ready to use. The solvent will depend on
the
formulation of the composition and the mode of use or administration. Suitable
solvents
for drug compositions are well known and are available in the literature.
The kit, in one set of embodiments, may comprise a carrier that is
compartmentalized to receive in close confinement one or more container means
such as
vials, tubes, and the like, each of the compartments comprising one of the
separate
elements to be used in the method. For example, one of the compartments may
comprise
a positive control for an assay. Additionally, the left may include containers
for other
components of the compositions, for example, buffers useful in the assay.
3o The function and advantage of these and other embodiments of the present
invention will be more fully understood from the examples below. The following
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examples are intended to illustrate the benefits of the present invention, but
do not
exemplify the full scope of the invention.
EXAMPLE 1
In this example, circular dichroism (CD) was used to monitor changes in
conformation of model peptides from human neurofilament, NF-M17 (glu-glu-lys-
gly-
lys-ser-pro-val-pro-lys-ser-pro-val-glu-glu-lys-gly) (SEQ ID NO: 1) (Fig. 1)
when
exposed to certain compounds of the present invention. These compounds
included
certain hydroxy derivatives of organosilanes, as well as the monols, diols and
triols of
1o certain organosilicon compounds. These compounds were tested for their
ability to
restore the CD spectrum of NF-M17 to its original shape.
The experiments were performed as follows. Peptides containing a seventeen
amino acid region of the human neurofilament mid-sized subunit protein, NF-M17
were
synthesized at greater than 95% purity. For the CD titration, the peptides
were dissolved
in 2,2,2-trifluoroethanol (TFE) to a concentration of 0.4 mgfml (0.2 mM). The
aluminum solution (20 mM) was also prepared in TFE. Sodium metasilicate and
the
orthosilicate were dissolved in water. The sodium metasilicate solution was
acidified to
pH 6Ø The initial CD spectra collected contained primarily only information
about the
peptide. Incremental additions of aluminum ion were made until 8 equivalents
(addition
of 8 microliters) of the metal ion were added to the solution containing the
peptide. The
maximum conformational change at 8 equivalents of aluminum was then titrated
with
SiO44-. Additions to the solution were made as increments of peptide molar
equivalents
and did not exceed 32 equivalents. After each addition, the CD spectrum was
collected
and analyzed.
The following silantriols or their precursors were tested: 3-
aminopropylsilantriol
(APST), 3-(trihydroxysilyl)propyhnethylphosphonate sodium salt (TSPMP), n-
octyltrichlorosilane (OTCS) after hydrolysis in water, and 3-
cyanopropyltrichlorosilane
(CPTCS), after hydrolysis in water. The following silandiols or their
precursors were
also tested in this example: diphenylsilandiol (DPSD),
hexylmethyldichlorosilane
(HMDS), methylphenyldichlorosilane (MPDS), dichlorodiethylsilane (DCDES),
dichlorodiisopropylsilane (DCDIPS), and (dichloro)methylsilylbutyronitrile
(DCMSBN).
The following silanols or their precursors were also tested: potassium
trimethylsilanolate
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(PTMS), tent-butyldimethylsilanol (TBDMS), triethylsilanol (TES), and
benzyldiethylsilanol (BDS). APST, DPSD, and APTES were obtained from Gelest,
Inc.
(Tullytown, PA). TFE, TSPMP, PTMS, TBDMS, TES, TPS, DCDIPS, DCDES,
DCMSBN, and BDS were obtained from Sigma-Aldrich (St. Louis, MO). OCS and
CPTCS were obtained from Lancaster Synthesis (Windham, NH). These structures
are
shown in Fig. 2.
APST (Fig. 2A), TSPMP (Fig. 2B), PTMS (Fig. 2K), TBDMS (Fig. 2L), TES
(Fig. 2M), and BDS (Fig. ZN) were each dissolved to a final concentration of
20 mM in
TFE. The addition of 2 microliters to 100 microliters of peptide solution
represented 2
1o equivalents.
OTCS (Fig. 2C), CPTCS (Fig. 2D), HMDS (Fig. 2F), DCDES (Fig. 2H),
DCDIPS (Fig. 2I), and DCMSBN (Fig. 2J) were each hydrolyzed in water and
diluted to
a final concentration of 20 mM. MPDS was first dissolved in 50% TFE in water
and
then made up to a final concentration of 20 mM. MPDS (Fig. 2G) was first
dissolved in
50% TFE in water and diluted to final concentration of 20 rnM. DPSD (Fig. 2E)
was
first dissolved in dimethyl sulfoxide (DMSO) and then made up to a final
concentration
of 20 mM in TFE. DMSO blanks (containing no peptide) were collected for each
dilution (0.04% to 1%).
The results of these experiments are summarized in Table 1. Figs. 3 and 4 show
2o control experiments using sodium metasilicate nonahydrate and sodium
orthosilicate,
respectively, as a source of the silicate ion. With sodium metasilicate, the
CD curve
showed some return to its original shape at about 32 equivalents (Fig. 3D).
Sodium
orthosilicate, however, showed a return to the original shape beginning at 4
equivalents
(Fig. 4C). At around 16 equivalents the CD spectrum with sodium orthosilicate
is
2s similar in shape to the original NF-M17 spectra (Fig. 4D).
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Table 1
Organosilanol Restore original spectra?
Triol
APST Yes
TSPMP (precipitation of peptide)
OTCS (gelation of OTCS)
CPTCS Yes
Diol
DPSD (DMSO interfered with spectra)
HMDS Yes
MPDS Yes
DCDES Yes
DCDIPS Yes
DCMSBN Yes
Monol
PTMS No
TBDMS No
TES No
BDS No
The APST solution used was a 22-25% by weight solution in water. The APST
solution was able to restore the CD spectrum of NF-M17/aluminum to its
original shape,
with better recovery at higher equivalents (Fig. 5). The APST solution also
showed
improved chelation of aluminum compared to sodium orthosilicate (Fig. 6).
The TSPMP solution used was a 42% by weight solution in water. This triol did
not successfully restore the original spectra of NF-M17. The incremental
addition of
TSPMP solution precipitated the peptide out of solution (data not shown).
to The OTCS solution used was a 100% solution. With the addition of water, the
organochlorosilane solution underwent gelation and did not restore the
original spectra of
the NF-M17 peptide (data not shown).
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The CPTCS solution used was as a 100% solution. The CPTCS solution did not
gel on addition of water, and the solution restored the CD spectrum of NF-
MI7/aluminum to its original shape at around 32 equivalents (Fig. 7).
DPSD did not restore the original spectra of NF-M17. The incremental addition
of DPSD solution precipitated the peptide out of solution (data not shovnm).
In contrast,
solutions of IMS (Fig. 8), MPDS (Fig. 9), DCDES (Fig. 10), DCDIPS (Fig. 11),
and
DCMSBN (Fig. 12) each restored the original CD spectrum of NF-Ml7/aluminum to
its
original shape at around 32 equivalents.
Solutions of PTMS, TBDMS, TES, and BDS (data not shown) each did not
1o restore the original spectra of the NF-MI7 peptide.
In conclusion, the organosilanes, the diols and triols, restored the original
CD
spectra of NF-M17, thus indicating the restoration of the original
conformation of NF-
M17. The diols and triols may form polyvalent crosslinked entities that may
favorably
bind and strip aluminum from NF-M.
EXAMPLE 2
This prophetic example illustrates a method for treating Alzheimer's disease
in a
human subject with a composition of the invention comprising an organosilicon
compound that inhibits interaction between aluminum and beta-amyloid.
2o The subject is given the composition orally, in the form of a pill, once a
day. The
dose concentration per day is 4.0 mcmol/kg. Administration is carried out for
a period of
about six months. This treatment interferes with further development of
neurofibrillary
tangles and senile plaques.
EXAMPLE 3
Amyloid peptide in TFE is believed to have a large degree of alpha-helical
structure that is changed to a beta-sheet structure by the presence of
aluminum ions.
That transformation can be seen in a CD spectrum as a flattening of the
signal. Reagents
that partially or fully restore the initial beta-amyloid signal can thus be
interpreted as the
3o binding of aluminum to the reagent, allowing the peptide to regain its
native alpha-helix
character.
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Amyloid peptide (human amyloid beta-protein 1-42, SynPep) was dissolved in a
solution of 80% trifluoroethanol ("TFE")/20% water at 10 mg/ml to make a stock
solution, stored at 4°C. The stock solution was diluted to 0.45 nm/ml
to 0.50 nm/ml in
TFE for use in these experiments. The molecular weight of the peptide was 4315
Da;
thus, 0.45 mg/ml is equivalent to 100 micromolar. Aluminum perchlorate was
dissolved
in TFE at a concentration of 10 mg/ml. The silicate test reagents were
typically
dissolved and hydrolyzed in water at 60 mM.
The CD spectrum was determined for each sample as follows. The sample was
placed in a JASCO J-810 spectropolarimeter, in a cuvette having a volume of
100 ml,
1o and a path length of 500 mM. The sensitivity of the instrument was
approximately 100
millidegrees. Each spectrum was scanned with a wavelength range of between
about 180
nm to about 260 nm, or between about 180 nm to about 280 nm. The data pitch
was
about 0.2 nm. The scan settings were performed under continuous scanning, at
about 50
nm/min, with a response of 1 second. The data presented are data from two
is accumulations.
Initially, TFE alone was scanned as a control to confirm the standard
spectrum.
Next, beta-amyloid peptide alone was scanned at the start of each reagent
test. Then, 2
to 4 microliter aliquots of 10 mM aluminum perchlorate were added by a 2-20
microliter
micropipettor and new scans were recorded. Mixing within the cuvette done with
a 100
2o microliter pipettor. Other experiments (not shown) have revealed a large
flattening of
the peptide spectrum with the addition of 8 to 12 microliters of aluminum
(equaling
about 8 to 12 molar equivalents). Aliquots of a test compound were added to
the peptide
and aluminum in the cuvette, 2 to 4 microliters at a time, mixing well and
assaying the
spectrum between each addition. This procedure was repeated for each compound.
The
25 cuvette was well rinsed 3 to 5 times with about 100 microliters of TFE
between assays.
The compounds tested in this example were: 3-cyanopropyltrichlorosilane
(CPTCS) (Fig. 2D), dichlorodiethylsilane (DCDES) (Fig. 2H),
dichlorodiisopropylsilane
(DCDIPS) (Fig. 2I), (dichloro)ethyhnethylsilane (DCEMS) (Fig. 20),
hexyhnethyldichlorosilane (HMDS) (Fig. 2F), (dichloro)methylsilylbutyronitrile
3o (DCMSBN) (Fig. 2J), dichlorosilacyclobutane (DCSCB) (Fig. 2P), 1,7-dioxa-6-
sila-
spiro[5.5]undecane (SDSU) (Fig. 2Q), sodium orthosilicate,
triethoxysilylbutyronitrile
(TESB) (Fig. 2R), triethoxysilylpropionitrile (TESP) (Fig. 2S),
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trihydroxysilylpropylmethyl phosphonate (TSPM) (Fig. 2B), triethylsilanol
(TES) (Fig.
2M), tetrakis(dimethylamino)silane ("tetrakis") (Fig. 2T), and
tetraacetooxysilane (TAS)
(Fig. 2U). These compounds were obtained from Gelest (Morrisville, PA), Sigma-
Aldrich (St. Louis, MO), Lancaster Synthesis (Windham, NH), Flulca (St. Louis,
MO),
and Alpha Aesar (Ward Hill, MA).
Fig. 13 illustrates the effect of aluminum on the amyloid peptide. In Fig. I3,
the
CD spectrum of amyloid peptide decreases with higher concentrations of
aluminum.
Fig. 14 illustrates the effect of CPTCS on the almninum-amyloid peptide
system.
In Fig. 14, the addition of 12 equivalents of aluminum to the solution
containing the
1o amyloid peptide causes a major reduction in the CD spectrum. However, the
further
addition of CPTCS is able to restore the CD spectrum of the peptide. Moderate
reversal
was seen at 6 equivalents and 12 equivalents, while almost full reversal of
the effects of
aluminum on the peptide was seen with the addition of 24 equivalents of CTPCS.
Similar results were seen with DCDES. In Fig. 15, the addition of 8
equivalents
15 of aluminum caused a major reduction in the CD spectrum of amyloid peptide,
while the
addition of DCDES to the system at least partially restored the CD spectrum
with greater
amounts of restoration with higher equivalencies of DCDES. Similarly, DCDIPS
(Fig.
16), DCEMS (Fig. 17), HMDS (Fig. I8), DCMSBN (Fig. 19), DCSCB (Fig. 20), SDSU
(Fig. 21), sodium orthosilicate (Fig. 22), TESB (Fig. 23), TESP (Fig. 24),
TSPMP (Fig.
20 25), TES (Fig. 26), tetrakis (Fig. 27), and TAS (Fig. 28) each at least
partially restored
the original CD spectrum of the peptide, after the peptide had been exposed to
aluminum.
EXAMPLE 4
25 In this example, the transport of various organosilicon compounds of the
invention across cell monolayers that mimic the blood-brain barrier as
demonstrated.
Two different cell lines were used as model blood-brain barrier systems: Caco-
2 cells
and bMVEC cells. Detection of the organosilicon compounds was performed using
inductively coupled plasma spectrometry (ICP), per EPA method 200.7, using an
3o ultrasonic nebulizer.
Caco-2 is a cell line derived from human intestinal epithelium, commonly used
for studies of molecular transport across epithelia with tight junctions. The
Caco-2 cells
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used in these experiments were from the laboratory of Dr. Neil Simister at
Brandeis
University, originating from the ATCC (American Type Culture Collection). The
cells
were grown in Dulbecco's Modified Eagle's Medium (DMEM), with 5% fetal bovine
serum, 50 microgram/ml gentamicin at 5% CO2, 37 °C. Cells grown in
Isgrove's
s medium and RPMI-1640 instead of DMEM showed similar times to reach
confluence
and similar morphology (data not shown). The Caco-2 cells formed electrically
tight
junctions, as assayed by measuring the electrical resistance with a World
Precision
Instruments EVOM-G.
The cells were grown in tissue culture flasks, and split (passaged) when
1o confluence reached about 4:1. Cells ware seeded for experiments onto
Corning Costar
Transwell inserts, polyester or polycarbonate, with 0.4 micrometer pores.
CeIIs on
transparent polyester membranes could be directly observed using phase
contrast
microscopy. The cells were fed fresh medium at intervals of every 2 to 4 days.
The cells
were used for assays when the electrical resistance of the cell monolayer was
at least 400
15 ohms/cm2.
Bovine microvascular epithelial cells are primary cells from bovine brain,
purchased frozen from Cambrex Bio Science. These cells were grown on collagen-
coated membrane inserts, overcoated with fibronectin. The medium used was
Endothelial Basal Medium 2 (Clonetics) supplemented with bECGF, ascorbic acid,
2o platelet poor horse serum, penicillin, streptomycin and fungizone (provided
as a kit by
Cambrex). One aliquot of cells was diluted and split to seed 48 6.5 mm
membranes
(corning Costar polyester, 0.4 micrometer pores). The cells were fed fresh
medium
every 2-3 days, and used when visually confluent.
Six compounds were tested for transport across the two cell lines in this
example:
2s SDSU, DCSCB, TSPM, TESB, DCMSBN, and DCEMS. Data from these experiments
can be seen in Figs. 29A and 29B (Caco-2 cells) and Fig. 30 (bMVEC). In Figs.
29A
and 29B, the transport of these organosilicon compounds are plotted as a
function of time
and hours. The starting concentrations on the apical side for each compound
range
between 1 mm and 10 mm. In all cases, a significant amount of transport was
observed,
3o across the Caco-2 cells, with more transport being observed for TESB,
DCMSBN, and
DCEMS (Fig. 29B) than TSPM, DCSCB, and SDSU (Fig. 29A).
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Fig. 30 illustrates transport of these compounds across the bMVEC cells. In
Fig.
30, data are plotted for transport after 4 h and after 24 h, for two different
donor
concentrations. In all cases, a significant amount of transport was observed,
with more
transport occurring for higher concentration apicals.
Thus, this example illustrates that various compounds of the invention can
successfully be transported across the blood-brain barrier.
EXAMPLE 5
This example illustrates a method of making 1,7-dioxa-6-sila-
spiro[5.5]undecane
(Fig. 2Q) in one embodiment of the invention.
A 2 liter 4-neck flask equipped with a dry-ice condenser, overhead stirring, a
pot
thermometer, and a funnel was charged with 54.29 g of SiCl4. 4-chloro-1-
butanol was
added through the funnel at a pot temperature below 40 °C over a period
of about 30 min.
The mixture was stirred at room temperature for about 4 hours. 250 ml of ether
was then
added, followed by 4.86 g of magnesium turnings. After stirring at room
temperature for
14 h, 125 ml of tetrahydrofuran ("THF") was added in 5 portions over a time
period of 1
h. After all of the magnesium turnings were consumed, another 4.86 g of
magnesium
was added, followed by another 125 ml of tetrahydrofuran, added dropwise. The
mixture was stirred at room temperature for 6 hours, then allowed to settle
overnight.
2o The superliquid was transferred into another flask, arid the salts were
washed with 125
ml of ether. The solutions were combined, then distilled using a short column.
5.32 g
(12.4% yield) of the desired product was obtained upon heating at a head
temperature of
55 °C at 8 mmHg.
Schematically, this reaction can be represented as follows:
cl + 1islcl4 Et~ o cl
Ho sl.~cl
CI ~Cl
CI
O O
,CI
CI S'~CI + Mg T' ' S~ +
Physical data for this reaction is as follows:
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Component4-chloro-SiCl4 Mg EtherTHF \ j MgCl2
s.
1-butanol
Molecular108.57 169.9024.3174.1272.11172.03 95.22
weight
Boiling 50-52 57.6 3S-3665-6755- 58
point
(C)
Specific 1.09 1.483 0.7060.8892,320
gravity
Moles 0.50 0.25 0.40 0.25
Weight 54.29 42.48 9.72 43.01
(g)
Volume 49.80 28.64 375 250
(ml)
While several embodiments of the invention have been described and illustrated
herein, those of ordinary skill in the art will readily envision a variety of
other means
and/or structures for performing the functions and/or obtaining the results
and/or one or
more of the advantages described herein, and each of such variations or
modifications is
deemed to be within the scope of the present invention. More generally, those
skilled in
the art will readily appreciate that all parameters, dimensions, materials,
and
configurations described herein axe meant to be exemplary and that the actual
1o parameters, dimensions, materials, and configurations will depend upon the
specific
application or applications for which the teachings of the present invention
are used.
Those skilled in the art will recognize, or be able to ascertain using no more
than routine
experimentation, many equivalents to the specific embodiments of the invention
described herein. It is, therefore, to be understood that the foregoing
embodiments are
presented by way of example only and that, within the scope of the appended
claims and
equivalents thereto, the invention may be practiced otherwise than as
specifically
described and/or claimed. The present invention is directed to each individual
feature,
system, material and/or method described herein. In addition, any combination
of two or
more such features, systems, articles, materials and/or methods, if such
features, systems,
2o articles, materials and/or methods are not mutually inconsistent, is
included within the
scope of the present invention.
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The definitions, as used herein, should be understood to control over
dictionary
definitions, definitions in documents incorporated by reference, and/or
ordinary
meanings of the defined terms.
It should also be understood that, unless clearly indicated to the contrary,
in any
s methods claimed herein. that include more than one act, the order of the
acts of the
method is not necessarily limited to the order in which the acts of the method
are recited.
In the claims, as well as in the specification above, all transitional phrases
such as
"comprising," "including," "carrying," "having," "containing," "involving,"
"holding,"
and the lilee are to be understood to be open-ended, i.e., to mean including
but not limited
1o to. Only the transitional phrases "consisting of and "consisting
essentially of ' shall be
closed or semi-closed transitional phrases, respectively, as set forth in the
United States
Patent Office Manual of Patent Examining Procedures, Section 2111.03.
