Note: Descriptions are shown in the official language in which they were submitted.
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INTERNATIONAL PATENT APPLICATION UNDER THE
PATENT COOPERATION TREATY
To all whom it may concern:
Be it known that Pui-Kwong CHAN and May Sung MAK
have invented certain new and useful improvements in
BLOCKING THE METASTASIS OF CANCER CELLS AND THE USES OF NEW
COMPOUNDS THEREOF
of which the following is a full, clear and exact description.
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BLOCKING THE METASTASIS OF CANCER CELLS
AND THE USES OF NEW COMPOUNDS THEREOF
This application claims benefit of U.S. Serial No. 61/038,277 filed March 20,
2008, U.S.
Serial No. 61/054,308, filed May 19, 2008, International App'l No.
PCT/US2008/002086,
filed February 15, 2008, International App'l No. PCT/US2007/077273, filed
August 30,
2007, U.S. Serial No. 60/890,380, filed on February 16, 2007, U.S. No.
60/947,705, filed
on July 3, 2007, and U.S. Serial No.11/683,198, filed on March 7, 2007, which
claims
benefit of U.S. Serial Nos. 60/795,417, filed on April 27, 2006, 60/841,727,
filed on
September 1, 2006, 60/890,380, filed on February 16, 2007, and International
Application No. PCT/US2006/016158, filed April 27, 2006, which claims the
benefit of
the priority of the following applications: (1) U.S. Serial Nos. 11/289142,
filed November
28, 2005, and 11/267,523, filed November 4, 2005; (2) International
Application No.
PCT/US05/31900, filed September 7, 2005 (which claims the priority of U.S.
Serial Nos.
60/617,379, filed October 8, 2004, 60/613,811, filed September 27, 2004, and
60/607,858, filed September 7, 2004); (3) U.S. Serial No. 11/131,551, filed
May 17,
2005; and (4) U.S. Serial No. 11/117,760, filed April 27, 2005. This
application also
claims benefit of U.S. Serial No.11/412,659, filed April 27, 2006, U.S. Serial
No.
10/906,303, filed February 14, 2005, and U.S. Serial No. 12/344,682, filed
December 29,
2008. The contents of these preceding applications are hereby incorporated in
their
entireties by reference into this application.
FIELD OF THE INVENTION
This invention provides methods and compositions for reducing the adhesion
protein in
cell and blocks the migration, metastasis of cancer cells or inhibits the
growth of
cancers or anti-angiogenesis; wherein the cancers comprise breast, leukocyte,
liver,
ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS,
melanoma,
renal, cervix, esophagus, testis, spleen, kidney, lymph, pancreas, stomach and
thyroid
cancers, wherein the adhesion proteins or receptors comprise fibronectin,
integrins
family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface
proteins,
polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
BACKGROUND OF THE INVENTION
The composition from Maesa balansae for anti-leishmanial is a United Nation
funding
project. This invention is providing methods for inhibiting cancer metastasis
or growth,
wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder,
prostate, skin,
bone, brain, leukemia, lung, colon, CNS, melanoma, renal, cervix, esophagus,
testis,
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spleen, kidney, lymph, pancreas, stomach and thyroid cancers, wherein the
method is
using the extract, composition and compounds from Maesa balansae, Barringtonia
acutangula, Xanthoceras Sorbifolia, Harpullia, Aesculus hippocastanum.
SUMMARY OF THE INVENTION
This invention is providing methods of using the extract, composition and
compounds
from Maesa balansae and Barringtonia acutangula, Xanthoceras Sorbifolia,
Harpullia,
Aesculus hippocastanum for reducing adhesion protein, for inhibiting cancer
metastasis,
wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder,
prostate, skin,
bone, brain, leukemia, lung, colon, CNS, melanoma, renal, cervix, esophagus,
testis,
spleen, kidney, lymph, pancreas, stomach and thyroid cancers.
This invention provides a method for modulating the adhesion of cancer cell
and
blocking their migration, metastasis or inhibiting the growth of cancers or
anti-
angiogenesis, wherein the adhesion protein and their receptors comprise
fibronectin,
integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell
surface
proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and
FAK.
This invention provides a method of antiprotozoal comprising treating
leishmaniases,
amoebiasis, trypanosomiasis, toxoplasmosis and malaria.
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DETAILED DESCRIPTION OF THE FIGURES
Figure 1: Analysis of genesis of blood vessel in xenograft tumor treated with
compound Y. Figure A and B show the tumor sections taking from mice without
Xanifolia Y treatment. Figure C and B show the tumor sections taking from mice
with
Xanifolia Y treatment. More blood vessels were observed in the control Groupl
than
those in the drug-treated Group 2
Figure 2: Experiment shows that Y10 is cytotoxic to Leishmania Major
(promastigotes)
with IC50 approximately equal to 15ug/ml.
Figure 3: Shows the inhibition activity of compound Y, X, ACH-Y and AKOH-Y
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DETAILED DESCRIPTION OF THE INVENTION
This invention provides methods and compositions for modulating the gene
expression
to cure diseases or reduce the syndrome of diseases, wherein the modulating
comprises positive and negative regulating. In an embodiment, the method
comprises
5 inhibiting the gene expression. In an embodiment the method comprises
stimulating the
gene expression.
This invention provides methods and compositions for inhibiting the migration,
metastasis or growth of cancers or anti-angiogenesis, wherein the methods
comprise
affecting the gene expression, wherein comprise affecting the adhesion
proteins or their
receptors, reducing adhesion protien, or inhibiting the expression or
secretion of
adhesion proteins, wherein the adhesion proteins comprise fibronectin,
integrins family,
Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins,
polyglycans,
cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
This invention provides methods and compositions for inhibiting the migration,
metastasis or growth of cancers or anti-angiogenesis, wherein the methods
comprise
affecting the gene expression, wherein comprises stimulating the gene
expression.
This invention provides a method for altering the characteristic of cancer
cell membrane
resulting in blocking the migration, metastasis of cancer cells or inhibit the
growth of
cancers or anti-angiogenesis, wherein the method comprises reducing adhesion
protiens or their receptors, wherein the adhesion proteins comprise
fibronectin,
integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell
surface
proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and
FAK.
This invention provides methods, processes, compounds and compositions of
reducing
adhesion protein of cells, wherein the adhesion proteins comprise fibronectin,
integrins
family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface
proteins,
polyglycans, cadherin, heparin, tenascin, CD54, CAM, elastin and FAK. In an
embodiment, methods comprise inhibiting the gene expression. In an embodiment,
this
invention provides a method of reducing the secretion of fibronectin. In an
embodiment
the method can block the migration, metastasis of cancer cells or inhibit the
growth of
cancers or anti-angiogenesis, wherein the cancers comprise breast, leukocyte,
liver,
ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS,
melanoma,
renal, cervix, esophagus, testis, spleen, kidney, lymph, pancreas, stomach and
thyroid
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cancer. In an embodiment, the method is contracting the said cell with
compound
selected from Mbl, Mb2, Mb2.1, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9, Mbl 0, Mbl
1,
Mb12 and Mb13, ACH-Z4, ACH-Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X,
ACH-E, Bat, Ba2, Ba3, Ba4, Ba5, Ba6, Ba7, Ba8, Ba9, Bal 0, Bal 1, Ba12, Ba13,
Ba14,
Bal 5, Bal 6, Bal 7, Xanifolia Y0, Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia
(x), Escin or
Aescin or a salt, ester, metabolite thereof and Compound A to X and Al to X1
in the
application.
This invention provides a method of altering the characteristic of cancer cell
membrane,
wherein the method comprises altering the secretion of adhesion proteins,
wherein the
adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin,
collagen,
laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin,
tenascin,
CD 54, CAM, elastin and FAK. In an embodiment, the methods, processes,
compounds
and compositions comprises blocking, suppressing or inhibiting the expression
or
secretion of adhesion protein, wherein the adhesion proteins . In an
embodiment, the
methods, processes, compounds and compositions is interacting with adhesion
protein,
wherein the adhesion proteins. In an embodiment the methods, processes,
compounds
or compositions can block the migration, metastasis of cancer cells or inhibit
the growth
of cancers or anti-angiogenesis, wherein the cancers comprise breast,
leukocyte, liver,
ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS,
melanoma,
renal, cervix, esophagus, testis, spleen, kidney, lymph, pancreas, stomach and
thyroid
cancer. In an embodiment, the method is contracting the said cell with
compound
selected from Mbl, Mb2, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9, MblO, Mb11, Mb12
and Mb13,, ACH-Z4, ACH-Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-E,
Bat, Ba2, Ba3, Ba4, Ba5, Ba6, Ba7, Ba8, Ba9, Bal 0, Bal 1, Ba12, Ba13, Ba14,
Ba15,
Bal 6, Ba 17, Xanifolia Y0, Y1, Y2, Y, Y7, Y8, Y9, Y10, Xanifolia (x), Escin
or Aescin or
a salt, ester, metabolite thereof and Compound A to X and Al to X1 in the
application.
The adhesion proteins help cancer cell adhesion, invasion or metastasis,
wherein the
cancers comprise ovarian cancer. Reducing the adhesion proteins will reduces
the
metastasis of cancers.The fibronectin is one of the key factors in the biology
of epithelial
ovarian cancers. The reducing of fibronectin will inhibit the metastasis of
cancer cells.
This invention provides a method and composition for inhibiting the secretion
of
adhesion protein comprising fibronectin in order to cure the diseases, wherein
the
diseases comprise inhibiting cancer growth, wherein the cancers comprise
breast,
leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia,
lung, colon,
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CNS, melanoma, renal, cervix, esophagus, testis, spleen, kidney, lymph,
pancreas,
stomach and thyroid cancer. In an embodiment, the method is contracting the
said cell
with compound selected from Mbl, Mb2, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9, MblO,
Mb11, Mb12 and Mb13, ACH-Z4, ACH-Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0,
ACH-X, ACH-E, ACH-Mb5, ACH-Mb13, Bat, Ba2, Ba3, Ba4, Bas, Ba6, Ba7, Bab, Ba9,
Bal 0, Bal 1, Ba12, Ba13, Ba14, Ba15, Ba16, Ba 17, Xanifolia Y0, Y1, Y2, Y,
Y7, Y8,
Y9, Y10, Xanifolia (x), Escin or Aescin or a salt, ester, metabolite thereof
and
Compound A to X and Al to X1 in the application.
This invention provides a use of compound for manufacture of medicament or a
composition for inhibiting the growth, migration, metastasis of cancer and by
altering the
characteristics of membrane of cancer cell, wherein the characteristics
comprise
adhesion of proteins; wherein comprising the secretion of proteins or the
adhesion of
cells; wherein the characteristic comprise adhesion ability; wherein the
adhesion
proteins comprise fibronectin, integrins family, Myosin , vitronectin,
collagen, laminin,
Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin,
CD 54,
CAM, elastin and FAK; wherein the cancers comprise breast, leukocyte, liver,
ovarian,
bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma,
renal,
cervix, esophagus, testis, spleen, kidney, lymph, pancreas, stomach and
thyroid cancer;
wherein the method is administering contacting the say cells with the extract,
compositions, saponins and compounds from Xanthoceras Sorbifolia, Harpullia,
Aesculus hippocastanum, Maesa balansae and Barringtonia acutangula for
inhibiting
cancer metastasis, wherein the cancers comprise breast, leukocyte, liver,
ovarian,
bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma,
renal,
cervix, esophagus, testis, spleen, kidney, lymph, pancreas, stomach and
thyroid
cancers; wherein extracts, compositions, saponins and compounds are prepared
from
the husks, branches, stems, leaves, kernels, roots, barks, fruit, seeds or
seed shells of
the herb or plant.
The present invention provides vaccine for cancer immunotherapy. The vaccines
comprise extract, compositions, compounds and saponins from Xanthoceras
Sorbifolia,
Harpullia, Aesculus hippocastanum, Maesa balansae and/or Barringtonia
acutangula. In
embodiment, the compounds can be obtained from synthesis, semi-synthesis or
modification. The method comprises administering to the said subject and
effective
amount of vaccine for enhancing the immune response. The vaccines comprise
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saponins isolated from Xanthoceras Sorbifolia, Harpullia, Aesculus
hippocastanum,
Maesa balansae and/or Barringtonia acutangula.
The present invention provides adjuvant compositions for cancer curing. The
adjuvant
compositions comprise extract, compositions, compounds and saponins from
Xanthoceras Sorbifolia, Harpullia, Aesculus hippocastanum, Maesa balansae
and/or
Barringtonia acutangula. The method comprises administering to the said
subject and
effective amount of the above adjuvant compositions for enhancing the immune
response. The use of vaccine compositions comprise inhibiting cancer
metastasis,
wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder,
prostate, skin,
bone, brain, leukemia, lung, colon, CNS, melanoma, renal, cervix, esophagus,
testis,
spleen, kidney, lymph, pancreas, stomach and thyroid cancers.
The present invention provide a use of compound for manufacture of medicament
or
methods for making vaccine, wherein the vaccine comprise compounds or saponins
from Xanthoceras Sorbifolia, Harpullia, Aesculus hippocastanum, Maesa balansae
and/or Barringtonia acutangula, wherein the vaccine can be used for inhibiting
cancer
growth, wherein the vaccine is having immune adjuvant activity, wherein the
saponins
comprise Xanifolia Y0, Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or
Aescin or
a salt, ester, metabolite thereof. In an embodiment the saponin may be
selected from
formulas (1 A), (1 B), (1 C), (1 D), (1 E), (1 F), (1 G), (1 H), (1 J), (1 K),
(1 L). In an embodiment
the compound(s) are selected from Compound Z1 to Z13 in the application. In an
embodiment the saponin comprise Mbl, Mb2, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9,
MblO, Mbl l , Mb12 and Mb13,. In an embodiment, the compound comprises a
triterpene backbone, two angeloyl groups and sugar moiety. In an embodiment
the
compound(s) are selected from Compound A to X and Al to X1 in the application.
In an
embodiment the compound(s) are selected from ACH-Z4, ACH-Yl 0, ACH-Y2, ACH-Y8,
ACH-Y7, ACH-Y0, ACH-X, ACH-E, ACH-Mb5, and ACH-Mb12. In an embodiment the
saponins comprise Bat, Ba2, Ba3, Ba4, Bas, Ba6, Ba7, Bab, Ba9, Ba10, Ball,
Ba12,
Ba13, Ba14, Bal5, Ba16 and Ba 17. In an embodiment the compound(s) are
selected
from Xanifolia Y0, Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or
Aescin or a salt,
ester, metabolite thereof. In an embodiment, this invention provides a method
for
antiparasitics by using the above compounds, wherein the antiparasitics
comprise
inhibiting leishmaniases, amoebiasis, trypanosomiasis, toxoplasmosis or
malaria;
wherein a method comprises contacting cells with an effective amount of an
isolated,
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purified or synthesized compound, or its salt, or ester thereof, selected from
the above
compounds.
This invention provides a use of compound for manufacture of medicament or a
method
for pharmaceutical composition useful for inducing an immune response to and
antigen
in an individual comprising the saponin composition from Xanthoceras
Sorbifolia,
Harpullia, Aesculus hippocastanum, Maesa balansae or Barringtonia acutangula
or
synthesis. The present invention provide methods for enhancing an immune
response
to an antigen in an individual comprising administering an effective amount of
saponins/compositions from Xanthoceras Sorbifolia, Harpullia, Aesculus
hippocastanum,
Maesa balansae and/or Barringtonia acutangula, or the saponin comprise
Xanifolia YO,
Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or Aescin or a salt,
ester, metabolite
thereof, or the saponin may be selected from formulas (1 A), (1 B), (1 C), (1
D), (1 E), (1 F),
(1 G), (1 H), (1 J), (1 K), (1 L). In an embodiment the compound(s) are
selected from
Compound Z1 to Z13 in the application. In an embodiment the saponin comprise
Mbl,
Mb2, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9, Mbl 0, Mbl 1, Mb12 and Mb13, In an
embodiment the compound(s) are selected from Compound A to X and Al to X1 in
the
application. In an embodiment the composition(s) are selected from ACH-Z4, ACH-
Y10,
ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-E, ACH-Mb5, and ACH-Mb12. In an
embodiment the saponins comprise Bat, Ba2, Ba3, Ba4, Ba5, Ba6, Ba7, Ba8, Ba9,
Bal 0, Bal 1, Ba12, Ba13, Ba14, Ba15, Ba16, Ba17.
This invention is providing methods or a use of compound for manufacture of
medicament for modulating adhesion or angiogenesis of cancer cells,
antiparasitics,
enhancing an immune response, providing adjuvant activities or providing
vaccine
activities, inhibiting cancer metastasis or growth, of using the extract,
composition and
compounds from Maesa balansae, wherein the cancers comprise breast, leukocyte,
liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon,
CNS,
melanoma, renal, cervix, esophagus, testis, spleen, kidney, lymph, pancreas,
stomach
and thyroid cancers; In an embodiment the method is modulating the
phosphatidylinositol signaling system, regulate the gene expression of RGS4 ,
LEPR,
ICFBP3, ANGPT2, GPNMB, NUPR1 or LOC100126784. The compounds can be
purified from natural resource comprising Xanthoceras Sorbifolia, Harpullia,
Aesculus
hippocastanum, Maesa balansae or Barringtonia acutangula, or synthesized. The
compounds comprise following:
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(Our purification methods and biological assays including the MTT assay in
International
Application No. PCT/US05/31900, filed September 7, 2005, U.S. Serial No.
11/289142,
filed November 28, 2005, and U.S. Serial No. 11/131551, filed May 17, 2005,
and
PCT/US2008/002086, 1188-ALA-PCT, filed February 15, 2008, the contents of
which
5 are incorporated herein by reference)
Ra R,
O
Rz
OH
H~OH O COOH R'
00
HO O O HO
CH, rrOH yyO
H
'C HO HO O O H
CH3
OH
HO OH
wherein R1 is O(C=O)C(CH3)=CH(CH3), R2 is (E) O(C=O)CH=CH-C6H5, R3 is OH,
R4 is OH, also named Mbl; or wherein R1 is O(C=O)C(CH3)=CH(CH3), R2 is (Z)-
O(C=O)CH=CH-C6H5, R3 is OH, R4 is OH, also named Mb2; or wherein R1 is
10 O(C=O)C(CH3)=CH(CH3), R2 is (Z)-O(C=O)C(CH3)=CH-C6H5, R3 is OH, R4 is OH,
also named Mb2.1; or wherein R1 is O(C=O)C6H5, R2 is (E)-O(C=O)CH=CH-C6H5, R3
is OH, R4 is OH, also named Mb3; or wherein R1 is O(C=O)C6H5, R2 is (Z)-
O(C=O)CH=CH-C6H5, R3 is OH, R4 is OH, also named Mb4; or wherein R1, R2, are
O(C=O)C(CH3)=CH(CH3), R3 is OH, R4 is OH, also named Mb5; or wherein R1 is
O(C=O)C6H5, R2 is O(C=O)C(CH3)=CH(CH3), R3 and R4 are OH, also named Mb6;
or
R, R
R,
O
=.,.i Rz
OH Ry~-
HO IL-0 O R13 iz= R3
OH IQO
R, Rs
IõC~y Rs
HO O HO
rrOH yO
HO rO
H HO O OH
CH3
OH
HO OH
wherein R1 is O(C=O)C6H5, R2 is O(C=O)CH=CH-C6H5, R3, R4, R5 are OH, R6,
R7,R8, R9, R10, R11, R12 are CH3, R13 is COOH also named Mb7; or wherein R1 is
O(C=O)C6H5, R2 is O(C=O)CH=CH-C6H5, R3, R4, R5 are OH, R6 is CH2OH, R7, R8,
R9, R10, R11, R12 are CH3, R13 is COOH also named Mb8; or wherein R1 is
O(C=O)C(CH3)=CH(CH3), R2 is O(C=O)CH=CH-C6H5, R3, R4 are OH, R6, R7, R8,
R9, R10, R11, R12 are CH3, R13 is COOH also named Mb9; or wherein R1 is
O(C=O)C(CH3)=CH(CH3), R2 is O(C=O)CH=CH-C6H5, R3, R4 are OH, R6 is CH2OH,
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R7, R8, R9, R10, R11, R12 are CH3, R13 is COOH, also named Mb10; or wherein
R1,
R2, are O(C=O)C(CH3)=CH(CH3), R3 is OH, R4 is CH2OH, R5 is H, R6, R7, R8, R9,
R10, R11, R12 are CH3, R13 is COOH, also named Mb11; or wherein R1 is
O(C=O)C(CH3)=CH(CH3), R2 is O(C=O)CH=CH-C6H5, R3, R4 are OH, R6, R7, R8,
R9, R10, R11, R12 are CH3, R13 is COOCH3, also named Mb12;
or wherein R1 is O(C=O)C(CH3)=CH(CH3), R2 is (Z)-O(C=O)C(CH3)=CH-C6H5, R3 is
OH, R4 is OH, R5 is H, and R6, R7, R8, R9, R10, R11, R12 are CH3, R13 is COON,
also named Mb13; or
Hc
29 CH3
O O
H3C
25 26 CH2OH O CH3
SOH
COOH 27
O
O 24 X23
OH
HO OH HO
OH O
HO O
OH
OH
3-0-[[3-D-galactopyranosyl(1 ->2)]-[3- D-xylopyranosyl (1 ->3)-(3-D-
glucuronopyranosyl-
21-0-angeloyl, 22-O-angeloyl-3(3, 15a, 21[3, 22a, 28-pentahydroxyolean-12-ene,
named Ba 1
R,
R,
CH2OH
= OH
R3
O c
O
OH
HO OH HO
OH O
HO O
OH
OH
wherein R1 is O(C=O)C(CH3)=CH(CH3), R2 is O(C=O)C(CH3)=CH(CH3), R3 is
COOCH3, formula is 3-0-[[3-D-galactopyranosyl(1 ->2)]-[3- D-xylopyranosyl (1 -
3)-(3-D-
methylglucuronopyranosyl-21-O-angeloyl, 22-O-angeloyl-3(3, 15a, 21 [3, 22a, 28-
pentahydroxyolean-1 2-ene, named Ba 2; or wherein R1 is O(C=O)C6H5, R2 is
O(C=O)C(CH3)=CH(CH3), R3 is COOH, formula is: 3-0-[3-D-galactopyranosyl(1->2)]-
[3- D-xylopyranosyl (1 ->3)-[3-D-glucuronopyranosyl-21 -O-benzoyl, 22-O-
angeloyl-3(3,
15a, 21 [3, 22a, 28-pentahydroxyolean -12-ene, named Ba 3; or wherein R1 is
O(C=O)C6H5, R2 is O(C=O)C(CH3)=CH(CH3), R3 is COOCH3, formula is: 3-0-[(3-D-
galactopyranosyl(1 -2)]-[3- D-xylopyranosyl (1 -3)-(3-D-
methylglucuronopyranosyl-21-0-
benzoyl, 22-O-angeloyl-3(3, 15a, 21 [3, 22a, 28-pentahydroxyolean-1 2-ene,
named Ba 4;
or wherein R1 is O(C=O)C6H5, R2 is O(C=O)C6H5, R3 is COOH, formula is:
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3-0-[3-D-galactopyranosyl(1 >2)]-[3- D-xylopyranosyl (1 -43)-[3-D-
glucuronopyranosyl-
21-O-benzoyl, 22-O-benzoyl-3(3, 15a, 21[3, 22a, 28-pentahydroxyolean-12-ene,
named
Ba 5; or wherein R1 is O(C=O)C6H5, R2 is O(C=O)C6H5, R3 is COOCH3, formula is:
3-0-[[3-D-galactopyranosyl(1 ->2)]-[3- D-xylopyranosyl (1 -*3)-(3-D-
methylglucuronopyranosyl-21-O-benzoyl, 22-O-benzoyl-3(3, 15a, 21 [3, 22a, 28-
pentahydroxyolean-1 2-ene, named Ba 6; or wherein R1 is O(C=O)C6H5, R2 is
O(C=O)CH3CH3, R3 is COOH, formula is:
3-0-[[3-D-galactopyranosyl(1 ->2)]-[3- D-xylopyranosyl (1 ->3)-[3-D-
glucuronopyranosyl-
21-O-benzoyl, 22-O-isobutyryl-3(3, 15a, 21[3, 22a, 28-pentahydroxyolean-1 2-
ene,
named Ba 7; or wherein R1 is O(C=O)C6H5, R2 is OH, R3 is COOH, formula is:
3-0-[[3-D-galactopyranosyl(1 >2)]-[3- D-xylopyranosyl (1 -3)-(3-D-
glucuronopyranosyl-
21-O-benzoyl -3(3, 15a, 21 [3, 22a, 28-pentahydroxyolean-1 2-ene, named Ba 8
29
Sri Rt
6 6 CH2CH
OH
COON 2]
p O
24 23 O
OH
HO OH HO
OH O R' off
HO p
OH
OH
wherein R1 is OH , R2 is O-benzoyl, R3 is O-benzoyl,
3-0-[[3-D-galactopyranosyl(1 >2)]-[3- D-xylopyranosyl (1 -3)-[3-D-
glucuronopyranosyl-
21-0-[3,4-dibenzoyl--[3-D-xylopyranosyl]- 3[3, 15a, 21 [3, 22a, 28-
pentahydroxyolean-1 2-
ene, named Ba9
R1 is O-acetyl, R2 is O-benzoyl, R3 is O-benzoyl
3-0-[[3-D-galactopyranosyl(1->2)]-[3- D-xylopyranosyl (1-3)-[3-D-
glucuronopyranosyl-
21-0-[3,4-dibenzoyl--[3-D-xylopyranosyl]-22-O-acetyl- 3[3, 15a, 21 [3, 22a, 28-
pentahydroxyolean-12-ene, named Ba10
3-0-[R-D-galactopyranosyl(1 ->2)]-[3- D-xylopyranosyl (1 ->3)-(3-D-
glucuronopyranosyl-
21-0-[3-angeloyl, 4-benzoyl--(3-D-xylopyranosyl]- 3[3, 15a, 21[3, 22a, 28-
pentahydroxyolean-1 2-ene, named Ball
3-0-[[3-D-galactopyranosyl(1->2)]-[3- D-xylopyranosyl (1-3)-[3-D-
glucuronopyranosyl-
21-0-[3,4-diangeloyl--[3-D-xylopyranosyl]- 3[3, 15a, 21[3, 22a, 28-
pentahydroxyolean-
12-ene, named Ba12
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13
3-0-[3-D-galactopyranosyl(1 >2)]-[3- D-xylopyranosyl (1 -3)-[3-D-
glucuronopyranosyl-
21-0-[3-angeloyl, 4-tigloyl--[3-D-xylopyranosyl]- 3(3, 15a, 21[3, 22a, 28-
pentahydroxyolean-12-ene, named Ba13
2g
25 26 CH,OH
SOH
COON 27
R,
24 X23 O
HOOH OH HOO O
off O OH
H 0 0
OH
OH
Wherein R1 is OH R2 is O-benzoyl, R3 is O-benzoyl
3-0-[[3-D-galactopyranosyl(1->2)]-[3- D-xylopyranosyl (1-3)-[3-D-
glucuronopyranosyl-
21-0-[3,4-dibenzoyl--a-L-arabinopyranosyl]- 3[3, 15a, 21 [3, 22a, 28-
pentahydroxyolean-
12-ene, named Ba14
Wherein R1 is O-acetyl, R2 is O-benzoyl, R3 is O-benzoyl
3-0-[3-D-galactopyranosyl(1->2)]-[3- D-xylopyranosyl (1-3)-[3-D-
glucuronopyranosyl-
21-0-[3,4-dibenzoyl--a-L-arabinopyranosyl]-22-O-acetyl- 3(3, 15a, 21 [3, 22a,
28-
pentahydroxyolean-12-ene, named Ba15
3 2g
CH3
25 26 CH,OH O
NCH
COOH 27
O H3C 0
OH O za0
CH3
HO OH O oH O
Ho ~~ cH3 off
~H OH ,3-0-[[3-D-galactopyranosyl(1 --->2)]-[3- D-xylopyranosyl
(1 -~3)-[3-D-g Iucuronopyranosyl-21-O-[3-angeloyl-4-(3-benzoyl-2-methyl
butyryl)-a-L-
arabinopyranosyl]-22-O-acetyl- 3(3, 15a, 21(3, 22a, 28-pentahydroxyolean-1 2-
ene,
named Ba16
HC
3 CH3
` O O
HgC
ri 26 CH:OH O CH3
OH
COOH 27
O OH
O 0 2 X23
OH
HO O
OH H
OH O
H 0
O H OH ;3-0-[[3-D-galactopyranosyl(1->2)]-[3- D-
xylopyranosyl (1-*3)-(3-D-glucuronopyranosyl-21-0-angeloyl, 22-O-angeloyl-3(3,
15a,
16a, 213, 22a, 28-hexahydroxyolean-12-ene, also named Ba 17
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Anti-cancer activities:
The anti-cancer activity of Mb's compounds with ES2 cell: the IC50 of Mbl is
8ug/ml,
Mb2 is /ml, Mb3 is 8ug/ml, Mb4 is 15ug/ml, Mb5 is 6.5ug/ml, and Mb6 is
10ug/ml, Mb7
is 12ug/ml, Mb8 is 20ug/ml, Mb9 is 18ug/ml, Mb12 is 10ug/ml.
The anti-cancer activity of ACH's compounds with ES2 cell: the IC50 of ACH-Z4
is 40
ug/ml, ACH-Y3 is 20 ug/ml, ACH-Y10 is 20 ug/ml, ACH-Y2 is 35 ug/ml, ACH-Y8 is
35
ug/ml, ACH-Y7 is 65 ug/ml, ACH-YO is 20 ug/ml, ACH-X is 40ug/ml, ACH-E is 60
ug/ml
The anti-cancer activity of Ba compounds with ES2 cell: Bat is 5 ug/ml, Ba2 is
5 ug/ml,
Ba3 is 8 ug/ml, Ba 5 is 16 ug/ml, Ba7 is 11 ug/ml, Ba8 is 20 ug/ml, Ba9 is 12
ug/ml,
Ba17 is 5 ug/ml.
The anti-cancer activity of Xanifolia Y with cells: the IC50 of Y on
(bladder)TB9 cells is 5
ug/ml; IC50 of Y on (lung)H460 cells is 7.5 ug/ml; IC50 of Y on HeLa cells is
20 ug/ml;
IC50 of Y on skin cells is 12 ug/ml ; IC50 of Y on ES2(ovarian) cells is 5
ug/ml; IC50 of
pure Y on (Mouth) KB cells is 6 ug/ml;
IC50 of Z12 on ES2(ovarian) cells is 16 ug/ml; Z4 is 20ug/ml
IC50 of Mb5: (bladder)TB9 is 6.5ug/ml, (Prostate) DU145 is 7.6 ug/ml, (Lung)
H460 is
12 ug/ml (Liver) HepG2 is 6.5 ug/ml, (brain) T98G is 12 ug/ml, (Skin) SK-MELS
is 25
ug/ml, (Ovary)ES2 is 6.5 ug/ml, (Breast)MCF7 is 11 ug/ml.
IC 50 of ACH-Mb5: (bladder)TB9 is 5.7ug/ml, (Prostate) DU145 is 6.4 ug/ml,
(Lung)
H460 is 6.5 ug/ml (Liver) HepG2 is 4 ug/ml, (brain) T98G is 6 ug/ml, (Skin) SK-
MELS is
22 ug/ml, (Ovary)ES2 is 8 ug/ml, (Breast)MCF7 is 13 ug/ml.
This invention provides a method and composition for reducing of adhesion
protein to
cure the diseases, wherein the diseases comprise inhibiting cancer growth,
reducing leg
swelling, symptoms of chronic venous insufficiency, peripheral edema,
antilipemic,
chronic venous disease, varicose vein disease, varicose syndrome, venous
stasis,
expectorant, peripheral vascular disorders, cerebro-organic convulsion,
cerebral
circulation disorder, cerebral edema, psychoses, dysmenorrheal, hemorrhoids,
episiotomies, peripheral edema formation or postoperative swelling; for
reducing
symptoms of leg pain; for treating pruritis, lower leg volume, for reducing
symptoms of
pain; thrombosis, thromophlebitis; for preventing gastric ulcers
antispasmotic,
comprising administering to a subject, in need thereof, an effective amount of
the
composition of this invention.
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In an embodiment, the method comprises interacting with adhesion protien,
wherein the
adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin,
collagen,
laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin,
tenascin,
CD 54, CAM, elastin and FAK. In an embodiment, this invention provides a
method of
5 reducing the secretion of fibronectin.
In an embodiment, the method comprises reducing the adhesion ability of
adhesion
protein; wherein the adhesion proteins comprise fibronectin, integrins family,
Myosin,
vitronectin, collagen, laminin, Glycosylation cell surface proteins,
polyglycans, cadherin,
10 heparin, tenascin, CD 54, CAM, elastin and FAK.
In an embodiment, the method comprises modulating the secretion of adhesion
protien,
wherein the adhesion proteins comprise fibronectin, integrins family, Myosin,
vitronectin,
collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin,
heparin,
15 tenascin, CD 54, CAM, elastin and FAK. In an embodiment, the method
comprises
blocking the secretion of adhesion protien, wherein the adhesion protein
comprising
fibronectin. In an embodiment the method is administering contacting an
effective
amount of the compound selected from formulas in this application.
In an embodiment, this invention provides a method and composition for
modulating adhesion or angiogenesis of cancer cells, antiparasitics or
manufacturing an
adjuvant composition. In an embodiment, this invention provides a method of
antiprotozoal comprising treating leishmaniases, amoebiasis, trypanosomiasis,
toxoplasmosis and malaria.
This invention provides a use of compound for manufacture of medicament, a
method
and composition for altering the characteristic of adhesion protein to cure
diseases,
wherein the characteristic comprising adhesion ability, wherein the method
comprises
reducing the secretion of fibronectin, wherein the diseases comprise
inhibiting cancer
growth, reducing leg swelling, symptoms of chronic venous insufficiency,
peripheral
edema, antilipemic, chronic venous disease, varicose vein disease, varicose
syndrome,
venous stasis, expectorant, peripheral vascular disorders, cerebro-organic
convulsion,
cerebral circulation disorder, cerebral edema, psychoses, dysmenorrheal,
hemorrhoids,
episiotomies, peripheral edema formation or postoperative swelling; for
reducing
symptoms of leg pain; for treating pruritis, lower leg volume, for reducing
symptoms of
pain; thrombosis, thromophlebitis; for preventing gastric ulcers
antispasmotic,
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16
comprising administering to a subject, in need thereof, an effective amount of
the
composition of this invention; wherein the adhesion proteins comprise
fibronectin,
integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell
surface
proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and
FAK In an
embodiment the method is administering contacting an effective amount in a
subject
with the compound selected from formulas in this application.
A process and method for administration of the composition, wherein
administration is
by intravenous injection, intravenous drip, intraperitoneal injection or oral
administration;
wherein administration is by intravenous drip: 0.05-0.2mg/kg compound
dissolved in
250m1 of 10% glucose solution or in 250m1 of 0.9% NaCl solution, or by
intravenous
injection: 0.05-0.2mg/kg/day compound dissolved in 10-20m1 of 10% glucose
solution or
of 0.9% NaCl solution, or by intravenous drip: 0.1-0.2mg/kg/day compound
dissolved in
250m1 of 10% glucose solution or in 250m1 of 0.9% NaCl solution, or by
intravenous
injection: 0.1-0.2mg/kg/day compound dissolved in 10-20m1 of 10% glucose
solution or
of 0.9% NaCl solution, or by intraperitoneal injection (I.P.): 2.5mg/kg/day
compound
dissolved in 10% glucose solution or of 0.9% NaCl solution, or by oral
administration
wherein the dosage of mammal is 1-10mg/Kg, 10-30mg/Kg, 30-60mg/Kg, or 60-
90mg/Kg compound, or by intravenous injection or intravenous drip wherein the
dosage
of mammal is 0.01- 0.1 mg/Kg, 0.1-0.2mg/Kg, 0.2 - 0.4mg/Kg, or 0.4 - 0.6 mg/Kg
compound, or by intraperitoneal injection (I.P.) wherein the dosage of mammal
is 1-
3mg/Kg, 3-5mg/Kg, 4-6mg/Kg, or 6-10mg/Kg compound.
The methods and uses of an isolated, purified or synthesized compound or its
salt, ester,
metabolite or derivative thereof, having the formula of :
R15 Rio
R1
õ-IIR2
R11 R12 R
4
Rg
R13
R3
R50
R9 R10 also named (1 A),
wherein R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-
senecioyl, 0-
alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl
substituted 0-
alkanoyl, 0-alkanoyl substituted phenyl, 0-alkenoyl substituted phenyl, O-
aryl, O-acyl,
0-heterocylic, 0-heteroraryl, and derivatives thereof;
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17
R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, and derivatives thereof;
R4 represents CH2R6 or CORE, wherein R6 is selected from a group consisting of
hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O-dibenzoyl, O-benzoyl,
0-
alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl
substituted
phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-
heteroraryl, and
derivatives thereof; R3 is H or OH; R8 is H or OH;
R5 is a hydrogen, heterocyclic or sugar moiety(ies), wherein the sugar
moiety(ies) is/are
selected from a group consisting of glucose, galactose, rhamnose, arabinose,
xylose,
fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose,
sorbose,
tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic
acid, and
derivatives or combination thereof; wherein R9, R10, R11, R12, R13, R14, R15
are
independently attached a group selecting from CH3, CH2OH, CHO, COOH, COO-
alkyl,
COO-aryl, COO- heterocyclic, COO-heteroaryl, CH2Oaryl, CH2O- heterocyclic,
CH2O-
heteroaryl, alkyls group, hydroxyl, acetyl group, particularly CH3i wherein at
least two of
R1, R2 and R6 are compriseing a group selected from O-angeloyl, O-tigloyl, 0-
senecioyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl
substituted
O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-
aryl, O-acyl,
O-heterocylic, O-heteroraryl, and derivatives thereof; or at least one of R1,
R2, and R4
is a sugar moiety substituted with at least two groups selected from a group
consisting
of angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl,
alkenoyl, benzoyl
alkyl substituted alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl
substituted phenyl,
aryl, acyl, heterocylic, heteroraryl, and a derivative thereof; orwherein R4
is CH2R6;
wherein R1 and R2 independently consists an O-angeloyl group, or at least two
of R1,
R2 and R6 are O-angeloyl or at least one of R1, R2 or R6 is a sugar moiety
with two 0-
angeloyls; or wherein R5 is/are the sugar moiety(ies) selected from the
following sugars
and alduronis acids: glucose, galactose, rhamnose, arabinose, xylose, fucose,
allose,
altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose,
talose,
fructose, glucuronic acid, galacturonic acid; or their derivatives thereof, or
the
combination thereof; wherein the sugar preferably comprises glucuronic acid,
arabinose
and galactose. In an embodiment, wherein R5 is/are sugar moiety(ies) selected
from a
group consisting of glucose, galactose, arabinose, alduronic acid, glucuronic
acid,
galacturonic acid, and a derivative or combination thereof; in embodiment, the
acyl has
carbon 2 to 10.
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In an embodiment the method is administering contacting the compounds, wherein
the
compound is selected from the following:
a) An isolated, purified or synthesized compound is having structure
Xanifolia(Y),
Y~ o
OH O
"OH
COOH OH
~o O
" O
CH H
H CH "
OH or chemical name: 3-0-[[3-D-galactopyranosyl
(1 ->2)]-a-L-arabinofuranosy (1 ->3)-R-D-glucuronopyranosyl-21,22-O-diangel
oyl-3[3,
15a, 16a, 21 [3, 22(x, 28-hexahydroxyolean-12-ene;
b) An isolated, purified or synthesized compound is having structure Xanifolia
(Y1),
Y1
OH
H
COOH
0_ 1~
OH r fr
H OH CH,
OH
OH O \ ,IGI OH
OH ~(\ or chemical name: 3-0-[[3-D-galactopyranosyl (11 ->2)]-
a-L-arabinofuranosyl (1-*3)-(3-D-glucuronopyranosyl-21-O-(3,4-diangeloyl)-a-L-
rhamnophyranosyl-22-O-acetyl-33,16x, 21[3, 22(x, 28-pentahydroxyolean- 12-ene;
c) An isolated, purified or synthesized compound is having structure Xanifolia
(Y2),
Yz a
OH
"'OH
o COOH bH
OH OH
H OH
OH
" ZOHOH OH or chemical name: 3-0-[[3-D-glucopyranosyl-
(1-*2)]-a-L-arabinofuranosy (1-*3)-[3-D-glucuronopyranosyl-21,22-O-diangel oyl-
3(3,
15x, 16a, 21[3, 22(x, 24[3, 28-heptahydroxyolean-12-ene;
d) An isolated, purified or synthesized compound is having structure Xanifolia
(Y8),
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19
0
Y-8
OH p
'OH
H O
OH OH
HO 0
OH
O
HO
H
OH
OH or chemical name: 3-0-[18-glucopyranosyl (1-*2)]-
a-arabinofuranosyl (1 ->3)-Aglucuronopyranosyl-21, 22-O-diangeloyl-3,6, 16a,
21,6, 22a,
24,6, 28-hexahydroxyolean- 12-ene;
e) An isolated, purified or synthesized compound is having structure Xanifolia
(Y9),
0
Y9 "OH
OAc
"OH
O
COON
O ~
O O O C O
H ~(\ CH3
HO O
OH 0 C-O OH
HO IO ~l\
OH 0
pH OH or chemical name:3-O-[,6-galactopyranosyl (1 ->2)]-
a-arabinofuranosyl (1->3)-/3-glucuronopyranosyl-21-O-(3,4-diangeloyl)-a-
rhamnopyranosyl-28- O-acetyl-3,6, 16a, 21,6, 22a, 28-pentahydroxyolean-12-ene;
and
f) An isolated, purified or synthesized compound is having structure Xanifolia
(Y10),
O-c'
II
O
Y-10
OH O
"SOH
O CC OH O
Oyu
HO OH
OH
'to O OH or chemical name:
3-0-[,6-galactopyranosyl (1 -2)]-a-arabinofuranosyl (1 >3)-,6-
glucuronopyranosyl-21,
22-O-diangeloyl-3/3, 16a, 21,6, 22 a, 28-pentahydroxyolean- 12-ene.
g) An isolated, purified or synthesized compound is having structure Xanifolia
(Y0),
-r CH,
0 H25 21 ~HzoH
on
OH
OH O .a ,a
HO HO
HO
O 00
OH
H or chemical name: 3-0-[(3-D-
galactopyranosyl(1 ->2)]-a-L-arabinofuranosyl(1 ->3)-[3-D-glucuronopyranosyl-
21-0-
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angeloyl, 22-0-(2-methylpropanoyl)-3(3, 15a, 16a, 21[3, 22a, 28-
hexahydroxyolean-12-
ene,
h) An isolated, purified or synthesized compound is having structure Xanifolia
(X),
9 29 O
HC
\ ....."r,OOH3
26 CH,OH 0
0 OH
21
p
OH O a 23
HO HO
HO
0
Ho p
5 OH or chemical name: 3-0-{[,6-D-galactopyranosyl
(1- 2)]-[c-L-arabinofuranosyl (1- *3)]-J3-D-glucuronopyranoside butyl ester}-
21-O-acetyl-
22-O-angeloyl- 3/3,16a,21,6,22a,28-pentahydroxyolean- 12-ene.
i) An isolated, purified or synthesized compound is having structure (Y7),
9o ~H
0
OH H321 2.
0
OH 0
O OOOH 27 - OH ff
0 as o
HO HO
HO
on O
OH 0
10 OH or chemical name: 3-0-[f-D-galactopyranosyl-
(1--->2)]-a-L-arabinofuranosyl-(1--->3)-f3-D--glucuronopyranosyl-21-O-angeloyl-
28-0-2-
methylbutanoyl-3f3, 15 a, 16a, 21 fi, 22a, 28-hexahydroxyolean-12-ene
j) An isolated, purified or synthesized compound is having structure (ACH):
29
O - G_ 3 `` H30 _
0 CH3
" II
O
O
OH O 25 26 CH _OH 4j~ "'OH "OH
OH HO OH
15 H (ACH-Y); 24 '23 ACH-Z4
29 H3C- 30 29 H 3C
0 `CH3 O~CHa
0H,C OH3C
.......,ni0GH3 ....,.nõO CH3
25 26 CH20H O 25 26 CH20H O
OH = SOH
27 27
HO HO OH
2 23 ACH-Y10, HO X23 ACH-Y2;
30 HC H3C
29 30 29
0 CH3 0CH3
O H 0
.......'OH H3C
25 26 CHzOH O 25 26
OCH3
OH = : "OH 0
27 27 -
HO HO OH
H ACH-Y8; 2~23 ACH-Y7;
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21
30 29 HC H3C
pCH3 30 29 CH
O H3C O O
O
CH3
25 26 CH2OH p 25 26 CH2OH CH3
= OH = OH
27 = 27
HO OH HO
2 23 ACH-YO; 23 OH ACH-E;
H3C
CH,
30 29 0 H3C, CH3
:OH 0 0
0--LCH2
H3C O
H3C
25 26 CH,O 0 CH3 CH3 H3C
OH CH3 OH O CH3
27
HO HQ
2 23 ACH-X H3C "0H3 ACH-Mb5
OH p
0
11 0
0
HO ACH-Mb12
In an embodiment the method is administering contacting the compound, wherein
the
compound is selected from the following:
k) An isolated, purified or synthesized compound is having a structure:
,C H
9
D-~ CH3
D~' DH
21 C.
CH2OH O
O 0 COCH 27 OH DH
OH p
23
HO HO HO
OH
I) An isolated, purified or synthesized compound is having a structure:
H,O H
H ,O - H,
25 26 CH2OH o
0 OH
000H 27
0 OH
0 24 "03
HO H
OH 0
HO OH Y5
In an embodiment the method is administering contacting the compound, wherein
the
compound is isolated, purified or synthesized having a structure selected from
following
formulas:
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22
R,
~ "Rz
R7
R6
R5 R3
R4 (1 C),
wherein R1, R2 are individually selected of an 0-acetyl or O-angeloyl; wherein
the R3,
R4, R5, R6, R7 is hydrogen or hydroxyl
In an embodiment the method is administering contacting the compound in this
application comprising Xanifolia YO, Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia
(x), Escin
or Aescin or a salt, ester, metabolite thereof. In an embodiment the compound
may be
selected from formulas (1 A), (1 B), (1 C), (1 D), (1 E), (1 F), (1 G), (1 H),
(1 J), (1 K), (1 L). In
an embodiment, the compound comprises a triterpene backbone, two angeloyl
groups
and sugar moiety. In an embodiment the compound(s) are selected from Compound
A
to X and Al to X1 in the application. In an embodiment the compound(s) are
selected
from Compound Z1 to Z13 in the application. In an embodiment the method is
administering contacting the compound comprise of a triterpene wherein the
carbon
position 21, 21 has an unsaturated group and sugar moieties at carbon 3.
In an embodiment, methods and compounds of this application reducing the
adhesion
ability inhibit bacteria in colonization and regulate tropism of cells.
In an embodiment, reducing the adhesion ability of cell or viruses in order to
inhibit
viruses binding to host cells, wherein the viruses comprise HIV.
This invention provides a use of compound for manufacture of medicament, a
method
and composition for modulating adhesion or anti-angiogenesis of cancer
tumor, antiparasitics or manufacturing an adjuvant composition, wherein the
modulating
adhesion of cancer cell comprising modulating the secretion or expression of
adhesion
protein, wherein the adhesion proteins comprise fibronectin, integrins family,
Myosin ,
vitronectin, collagen, laminin, cadherin, heparin, tenascin, CD 54, CAM;
wherein the
modulating comprises reducing, inhibiting and stimulating, wherein modulating
adhesion
protein comprises reducing the fibronectin for inhibiting the metastasis or
growth of
cancer cells, wherein the cancer is selected from breast cancer, leukocyte
cancer, liver
cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone
cancer,
brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma
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23
cancer, and renal cancer; wherein the modulating adhesion of cancer cell
comprising
modulating the secretion or expression of adhesion protein, wherein the
adhesion
proteins comprise fibronectin, integrins family, Myosin , vitronectin,
collagen, laminin,
cadherin, heparin, tenascin, CD 54, CAM; wherein the modulating comprises
reducing,
inhibiting and stimulating; wherein the modulating angiogenesis comprises
inhibiting
and stimulating angiopoietin, wherein comprising angiopoietinl, angiopoietin
2,
angiopoietin 3, angiopoietin 4, angiopoietin 5, angiopoietin 6 and
angiopoietin 7;
wherein the angiopoietin comprising angiopoietin-like 1, angiopoietin-like 2,
angiopoietin
-like 3, angiopoietin-like 4, angiopoietin-like 5, angiopoietin-like 6 and
angiopoietin-like 7;
wherein the modulating comprises positive and negative regulating; wherein
modulating
angiopoietin comprises stimulating the angiopoietin 2 in order to inhibit
angiogenesis;
wherein modulating angiopoietin comprises inhibiting the angiopoietin 1 in
order to
inhibit angiogenesis; wherein modulating angiopoietin comprises inhibiting the
angiopoietin-like 1; wherein modulating angiopoietin comprises inhibiting the
angiopoietin-like 4; wherein the antiparasitics comprise inhibiting
leishmaniases,
amoebiasis, trypanosomiasis, toxoplasmosis or malaria, wherein the method are
is
administering contacting the compound in this application comprising Xanifolia
Y0, Y1,
Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or Aescin or a salt, ester,
metabolite
thereof. In an embodiment the compound may be selected from formulas (1 A), (1
B),
(1 C), (1 D), (1 E), (1 F), (1 G), (1 H), (1 J), (1 K), (1 L). In an
embodiment, the compound
comprises a triterpene backbone, two angeloyl groups and sugar moiety. In an
embodiment the compound(s) are selected from Compound A to X and Al to X1 in
the
application. In an embodiment the compound(s) are selected from Compound Z1 to
Z13
in the application. In an embodiment the compound(s) are selected from ACH-Z4,
ACH-
Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-E, ACH-Mb5 and ACHMb12.
In an embodiment the saponins comprise Bat, Ba2, Ba3, Ba4, Bas, Ba6, Ba7, Bab,
Ba9, Bal0, Bal1, Ba12, Ba13, Ba14, Ba15, Ba16, and Ba17. In an embodiment the
saponins comprise Mbl, Mb2, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9, Mbl 0, Mbl 1,
Mb12, and Mb13.
In an embodiment, the methods and compositions of this application can be used
for
manufacturing an adjuvant vaccine, wherein the methods and compositions are
used for
manufacturing an adjuvant vaccine in a subject, wherein the method is
administering
contacting the compound in this application comprising Xanifolia Y0, Y1, Y2,
Y, Y5, Y7,
Y8, Y9, Y10, Xanifolia (x), Escin or Aescin or a salt, ester, metabolite
thereof. In an
embodiment the compound may be selected from formulas (1 A), (1 B), (1 C), (1
D), (1 E),
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24
(1F), (1G), (11-1), (1J), (1K), (1 L). In an embodiment, the compound
comprises a
triterpene backbone, two angeloyl groups and sugar moiety. In an embodiment
the
compound(s) are selected from Compound A to X and Al to X1 in the application.
In an
embodiment the compound(s) are selected from Compound Z1 to Z13 in the
application.
In an embodiment the compound(s) are selected from ACH-Z4, ACH-YlO, ACH-Y2,
ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-E, ACH-Mb5 and ACH-Mb12. In an
embodiment the saponins comprise Bat, Ba2, Ba3, Ba4, Ba5, Ba6, Ba7, Ba8, Ba9,
Ba10, Ball, Ba12, Ba13, Ba14, Ba15, Ba16, and Ba 17. In an embodiment the
saponins comprise Mbl, Mb2, Mb3, Mb4, Mb5, Mb6, Mb7, Mb8, Mb9, MblO, Mbl l ,
Mb12 and Mb13. In an embodiment, this application provides an adjuvant
composition
comprising a saponin or compound selecting from above; wherein the composition
is
comprised of an immunostimulatory oligonuclcotide.
In an embodiment, the methods and compositions of this application can be used
for
manufacture of medicament for vaccine or antiviral agent for Enterovirus
comprising
EV71, wherein the method is administering contacting the cell or subject with
compounds selected in this application comprising Mbl, Mb2, Mb3, Mb4, Mb5,
Mb6,
Mb7, Mb8, Mb9, Mbl 0, Mbl 1, Mbl 2 and Mbl 3.
The composition comprises the bioactive compounds from natural plants or
synthesis.
The majority of the plants are from the Sapindaceae family, which has 140-150
genera
with 1400-2000 species. The program is based on our purification methods and
biological assays including the MTT assay See International Application No.
PCT/US05/31900, filed September 7, 2005, U.S. Serial No. 11/289142, filed
November
28, 2005, and U.S. Serial No. 11/131551, filed May 17, 2005, and
PCT/US2008/002086, 1188-ALA-PCT, filed February 15, 2008, the contents of
which
are incorporated herein by reference. The details of Analysis of gene
expression of ES2
cells after Y-treatment by Microarray, Data Analysis Methods and Western blot
in
PCT/US2008/002086, 1188-ALA-PCT, filed February 15, 2008, the contents of
which
are incorporated herein by reference
This invention provides a composition comprising an effective amount of
triterpenoidal
saponins named as Xanifolia Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, and YO or their
salt or
their derivatives. In an embodiment the saponins comprise Bat, Ba2, Ba3, Ba4,
Ba5,
Ba6, Ba7, Ba8, Ba9, Bal 0, Bal 1, Ba12, Ba13, Ba14, Ba15, Ba16, and Ba17 or
their
salt or their derivatives. In an embodiment the saponins comprise Mbl, Mb2,
Mb3, Mb4,
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Mb5, Mb6, Mb7, Mb8, Mb9, Mbl 0, Mbl 1, Mb12 and Mb13, or their salt or their
derivatives for modulating the adhesion protein, reducing adhesion protein or
reducing
the secretion of fibronectin, for treating chronic venous insufficiency,
peripheral edema,
antilipemic, chronic venous disease, varicose vein disease, varicose syndrome,
venous
5 stasis, expectorant, peripheral vascular disorders, cerebro-organic
convulsion, cerebral
circulation disorder, cerebral edema, psychoses, dysmenorrheal, hemorrhoids,
episiotomies, peripheral edema formation or postoperative swelling; for
reducing
symptoms of pain; for reducing symptoms of stomach pain; for reducing symptoms
of
leg pain; for treating pruritis, lower leg volume, thrombosis,
thromophlebitis; for treating
10 rheumatism; for preventing gastric ulcers antispasmotic; blocking the
migration,
metastasis of cancer cells or inhibiting tumor growth. In an embodiment the
method is
administering contacting the compound in this application comprising Xanifolia
Y0, Y1,
Y2, Y, Y5, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or Aescin or a salt, ester,
metabolite
thereof. In an embodiment the compound may be selected from formulas (1 A), (1
B),
15 (1 C), (1 D), (1 E), (1 F), (1 G), (1 H), (1 J), (1 K), (1 L). In an
embodiment, the compound
comprises a triterpene backbone, two angeloyl groups and sugar moiety. In an
embodiment the compound(s) are selected from Compound A to X and Al to X1 in
the
application. In an embodiment the compound(s) are selected from Compound Z1 to
Z13
in the application. In an embodiment the compound(s) are selected from ACH-Z4,
ACH-
20 Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-E, ACH-Mb5 and ACH-Mb12.
The compounds of this invention can be isolated from natural sources or
synthesized.
See experiments results in this application and see PCT/US05/31900, filed
September
7, 2006; U.S. Serial No. 10/906,303, filed February 14, 2005; International
Application
25 No. PCT/USO4/43465, filed December 23, 2004; International Application No.
PCT/US04/33359, filed October 8, 2004 and U.S. Serial No. 11/131551, filed May
17,
2005, PCT/US2007/077273, filed August 30, 2007, PCT/US2008/002086, 1188-ALA-
PCT, filed February 15, 2008, US61/038277 filed March 20, 2008, US61/054308,
filed
May 19, 2008, the contents of which are incorporated herein by reference.
Acid Hydrolysis of Saponin
15 mg Xanifolia-Y was dissolved in 1 ml of Methanol. 1 ml of 2N HCI was then
added.
The mixture was refluxed in 80C water bath for 5 hours. The solution was then
neutralized by adding 2 ml of 1 N NaOH (to final pH 4-6). The aglycone was
then
extracted with ethylacetate 3 ml x 2. The extracts were collected and pooled.
Further
isolation of aglycone (ACH-Y) was achieved by HPLC with isocratic elution of
80 -100%
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26
acetonitrile. Repeat the experiment with compound Z4, Y10, Y2, Y8, Y7, Y0, X,
and
ESCIN were obtained compounds ACH-Z4, ACH-Y10, ACH-Y2, ACH-Y8, ACH-Y7,
ACH-Y0, ACH-X, ACH-E, ACH-Mb12, ACH-Mb5.
In mild conditions, the saponin will be partial hydrolysis to a mixture of
products. The
procucts can be separated by HPLC. Also, specific partial hydrolysis can be
achieved
with enzymes. The R-glucosidase is good enzyme to cleave of the a-glucose from
saponin.
Removal of the acyl group by alkaline hydrolysis
mg of Xanifolia-Y was dissolved in 0.5 ml of 1 M NaOH. The solution was
incubated
in 80C water bath for 4 hours. It was cooled to room temperature before
neutralized with
0.5 ml 1 N HCI (adjust pH to about 3). The mixture was extracted with 2 ml 1-
butanol 3
times. The butanol fractions were collected and lyophilized. The hydrolyzed
saponin
15 with further purified with HPLC in a C-18 column eluted with 25%
acetonitrile.
OH
"OH
.....,,,,,=oH OH
"
HO o COO0
oH
O OH 0
-HO H O HO
HO OH O 0 HO " oM pry O
HO O
O Ho O O OH
HO O
OH OH
OH AKOH-Y; OH AKOH-Mb5
Compounds AKOH-Y and AKOH-Mb5 have lost anticancer activity.
20 This invention provides a use of compound for manufacture of medicament or
a method
of modulating the adhesion proteins or their receptors, reducing the adhesion
ability of
the cancer cells, wherein the modulating comprises the positive or negative
regulating.
In an embodiment, the adhesion proteins comprise fibronectin, integrins
family, Myosin,
vitronectin, collagen, laminin, Glycosylation cell surface proteins,
polyglycans, cadherin,
heparin, tenascin, CD 54, CAM, elastin and FAK. In an embodiment, the method
is
reducing the secretion of fibronectin. This invention provides a method of
blocking the
migration, metastasis of cancer cells or inhibiting cancer cell growth or
inhibiting
leishmaniases modulating adhesion or inhibiting angiogenesis of cancer
tumor, antiparasitics or manufacturing an adjuvant composition comprising
administering an effective amount of a pharmaceutical composition comprising a
composition comprises the molecular formula or compound in this invention. The
cancers comprise Leukemia cancer, Lung cancer, Colon cancer, CNS cancer,
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27
Melanoma cancer, ovarian cancer, renal cancer, Prostate cancer, Breast cancer,
bladder cancer, cervix cancer, liver cancer, bone cancer, brain cancer and
Skin cancer.
The compounds of this invention can be isolated from natural sources or
synthesized. In
an embodiment the method is administering contacting the compounds, wherein
the
compound is selected from the following:
(Z1) 3-0-[[3-D-galactopyranosyl(1 -2)]-a-L-arabinofuranosyl(1 -3)-(3-D-
glucuronopyranosyl-21-0-angeloyl, 22-0-(2-methylpropanoyl)-3(3, 15a, 16x,
21[3, 22a,
28-hexahydroxyolean-1 2-ene;
(Z2) 3-0-[/3-D-galactopyranosyl-(1-*2)]-a-L-arabinofuranosyl-(1-*3)-(3-D-
-glucuronopyranosyl-21-O-angeloyl-22-O-(angeloyl-2-methylbutanoyl) -30, 15 a,
16a,
21/3, 22a, 28-hexahydroxyolean-12-ene;
(Z3) 3-0-[[3-D-galactopyranosyl(1 ->2)]-a-L-arabinofuranosyl(1 ->3)-(3-D-
glucuronopyranosyl-21-O-(2-methylpropanoyl), 22-0-(2-m ethyl propanoyl)-3(3,
15a, 16a,
21[3, 22a, 28-hexahydroxyolean-12-ene;
(Z4) 3-0-[[3-D-galactopyranosyl(1 -2)]-a-L-arabinofuranosyl(1 ->3)-(3-D-
glucuronopyranosyl-21 -0-angeloyl, 22-O-benzoyl-3(3, 15a, 16a, 21 [3, 22a, 28-
hexahydroxyolean-1 2-ene;
(Z5) 3-0-[3-D-galactopyranosyl(1 -2)]-a-L-arabinofuranosyl(1 ->3)-(3-D-
glucuronopyranosyl-21-0-angeloyl, 22-O-angeloyl-3(3, 15a, 16x, 21 [3, 22a, 28-
hexahydroxyolean-1 2-ene;
(Z6) 3-0-[3-D-galactopyranosyl(1 -2)]-a-L-arabinofuranosyl(1 -3)-(3-D-
glucuronopyranosyl-21-O-(2-methyl pro panoyl)-O-benzoyl, 22-0-(2-
methylpropanoyl)-
3(3, 15a, 16a, 21[3, 22a, 28-hexahydroxyolean-12-ene;
(Z7) 3-0-[ 3-D-galactopyranosyl(1->2)]-a-L-arabinofuranosyl(1-3)-(3-D-
glucuronopyranosyl-21-O-(2-methylpropanoyl)-O-angeloyl, 22-0-(2-
methylbutanoyl) -
3(3, 15a, 16a, 21 [3, 22a, 28-hexahydroxyolean-12-ene;
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28
(Z8) 3-0-[[3-D-galactopyranosyl(1 -42)]-a-L-arabinofuranosyl(1 -3)-[3-D-
glucuronopyranosyl-21-O-benzoyl, 22-O-benzoyl-3(3, 15a, 16a, 21 [3, 22a, 28-
hexahydroxyolean-1 2-ene;
(Z9) 3-0-[[3-D-galactopyranosyl(1 -2)]-[3- D-xylopyranosyl (1 -3)-[3-D-
glucuronopyranosyl-21-0-angeloyl, 22-O-benzoyl-3[3, 15a, 16a, 21 [3, 22a, 28-
hexahydroxyolean-1 2-ene;
2CH
3 25 0
O H3C
25 26 CH3OH-_
O
= OH
COOH 27 OH
O
OH O 21 z3
HO
OH HO
OH O
o O
OH
OH Z 10
3-0-[[3-D-galactopyranosyl(1->2)]-[3- D-xylopyranosyl -(1-3)-[3-D-
glucuronopyranosyl-
21-0-(2-methyl propanoyl), 22-0-(2-m ethyl propanoyl)-3R, 15a, 16a, 21[3, 22a,
28-
hexahydroxyolean-1 2-ene;
"rIH,
zo
1'0 3 CH,
H,c 0
~25
o oH
o
zs
OH
HOO O
OH O
o
OH OH Z 1 1
3-0-[(3-D-galactopyranosyl-(1 -p2)]- [3- D-xylopyranosyl -(1 -3)-(3-D-
-glucuronopyranosyl-21-O-angeloyl-22-O-(angeloyl-2-methylbutanoyl) -3(3, 15 a,
16a,
21/3, 22a, 28-hexahydroxyolean-12-ene;
0- ~o
H~ CH,
CHSOH o
COOH 27 OH
o o
OH
Ho H
OH o.H O
O, O
OHOHHJ\I Z1 2,
3-0-[[3-D-galactopyranosyl(1 ->2)]-[3- D-xylopyranosyl (1 ->3)-(3-D-
glucuronopyranosyl-
21-0-angeloyl, 22-0- tigloyl -3[3, 16a, 21[3, 22a, 28-pentahydroxyolean-12-
ene;
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29
0
oH o
HO' HO o"
HO
0
Ho OH 0
OH Z13
3-0-[[3-D-galactopyranosyl(1 -2)]-a-L-arabinofuranosyl(1 ->3)-3-D-
glucuronopyranosyl-
21-0-angeloyl, 22-0- tigloyl -3(3, 15a, 16a, 21 [3, 22a, 28-hexahydroxyolean-
12-ene;
This invention provides uses of a compound for manufacture of medicament
selected
from formula (1 B), for modulating, regulating or interact with the adhesion
protien,
wherein the adhesion proteins comprise fibronectin, integrins family, Myosin,
vitronectin,
collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin,
heparin,
tenascin, CD 54, CAM, elastin and FAK. In an embodiment, this invention
provides a
method of reducing the secretion of fibronectin, modulating adhesion or
angiogenesis of
cancer cells, antiparasitics, enhancing an immune response, providing adjuvant
activities or providing vaccine activities, inhibiting cancer metastasis or
growth,using the
compounds selected for the following:
30 29
ORS
ni OR2
25 26
R4
Re
27
R5C R3
23`. 24 also named as (1 B),
or a salt, ester, metabolite or derivative thereof, wherein R1 comprises a
group selected
from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, dibenzoyl,
benzoyl, alkanoyl,
alkenoyl, benzoyl alkyl substituted alkanoyl, acyl, aryl, heterocylic,
heteroraryl,
alkenylcarbonyl and derivatives thereof; R2 comprises a group selected from
hydrogen,
angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl,
alkenoyl, benzoyl
alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl,
alkenylcarbonyl and
derivative thereof; R4 represents CH2OR6 or COOR6, wherein R6 is selected from
hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl,
alkanoyl,
alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic,
heteroraryl and
derivative thereof; R3 is H or OH; wherein at least one of R1, R2,and R6
comprises a
group selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl,
alkanoyl,
alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic,
heteroraryl and
derivative thereof; R5 comprises a hydrogen or sugar moiety, wherein the sugar
moiety
comprises at least one sugar of, but is not limited to, D-glucose, D-
galactose, L-
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rhamnose, L-arabinose, D-xylose, alduronic acid: D-glucuronic acid, D-
galacturonic acid
or a derivative thereof, or the combination thereof.
In an embodiment, R1 comprises a sugar moiety wherein substituted with two
groups
5 selecting from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl,
alkanoyl, alkenoyl,
benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic heteroraryl and a
derivative
thereof. In an embodiment, R1 comprises a sugar moiety wherein substituted
with at
least one group selecting from angeloyl, acetyl, tigloyl, senecioyl, benzoyl,
dibenzoyl,
alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl,
heterocylic, heteroraryl
10 and a derivative thereof. In an embodiment, R2 comprises a sugar moiety
wherein at
least one group is selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl,
benzoyl,
dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl,
heterocylic,
heteroraryl and a derivative thereof. In an embodiment, R2 comprises a sugar
moiety
or a side chain wherein at least two groups are selected from angeloyl,
acetyl, tigloyl,
15 senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl
substituted
alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof. In an
embodiment,
R4 comprises CH2OR6 or COOR6 wherein R6 is a sugar moiety which comprises at
least one group selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl,
dibenzoyl,
alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl,
heterocylic, heteroraryl
20 and a derivative thereof. In an embodiment, R4 comprises CH2OR6 orCOOR6,
wherein
R6 is a sugar moiety which comprises at least two groups selected from
angeloyl, acetyl,
tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl
substitutedalkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative
thereof. In an
embodiment, R4 comprises CH2OR6 or COOR6, wherein R6 is a sugar moiety which
25 comprises at least two groups selected from angeloyl, acetyl, tigloyl and
senecioyl. In an
embodiment, R4 comprises CH2OR6 or COOR6 of formula (1 B), at least two of R1,
R2
and R6 comprise the group selected from angeloyl, acetyl, tigloyl, senecioyl,
benzoyl,
dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl,
heterocylic,
heteroraryl and a derivative thereof. In an embodiment, R4 comprises CH2OR6 or
30 COOR6 of formula (1B), wherein at least two of R1, R2 and R6 comprise
angeloyl,
benzoyl, alkenoyl, or a derivative thereof. In an embodiment, R4 is a side
chain
comprising CH2000CH3, CH2O00-alkyl, CH2OH, COOH, angeloyl, acetyl, tigloyl,
senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl
substituted
alkanoyl, aryl, acyl, heterocylic or heteroraryl, alkanoyl substituted phenyl,
alkenoyl
substituted phenyl, or a derivative thereof. In a further embodiment, R5
comprises a
sugar moiety, wherein the sugar moiety comprises one or more sugar of, but is
not
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31
limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose,
altrose,
gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose,
fructose, or
alduronic acid: glucuronic acid, galacturonic acid, or derivatives thereof, or
the
combination thereof. In an embodiment, R5 comprises a sugar moiety or a group
capable of performing the function of the sugar moiety. In an embodiment, the
R5
represents H. In an embodiment, R4 represents H, OH or CH3. In an embodiment,
position C23, C24, C25, C26, C29 and C30 of the compound independently
comprise
CH3, CH2OH, CHO, COOH, COOa-lkyl, COO-aryl, COO-heterocyclic, COO-heteroaryl,
CH2Oaryl, CH2O- heterocyclic, CH2O- heteroaryl, alkyls group, acetyl group or
derivatives thereof, particular CH3. In an embodiment, R1 and R2 independently
comprise an angeloyl group. In an embodiment, R1 is a sugar moiety or a side
chain
which comprise two angeloyl groups. In an embodiment, R1 and R2 independently
comprise a benzoyl group. In an embodiment, R1 is a sugar moiety which is
substituted
with two benzoly groups. In an embodiment, R3 represents H or OR In an
embodiment,
R8 may be OR In an embodiment, the 0 at C21, 22 may be replaced by N. In an
embodiment, this invention provides a method of reducing the secretion of
fibronectin;
wherein the medicament is for inhibiting tumor or cancer cell growth and for
treating
cancer, wherein the cancers comprise breast cancer, leukocyte cancer, liver
cancer,
ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer,
brain cancer,
leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal
cancer or cervix cancer. Substitution, deletion and/or addition of any group
in the above-
described compounds by other group(s) will be apparent to one of ordinary
skill in the
art based on the teachings of this application. In a further embodiment, the
substitution,
deletion and/or addition of the group(s) in the compound of the invention does
not
substantially affect the biological function of the compound.
This invention provides uses, methods, processes, compounds and compositions
for
modulating adhesion or angiogenesis of cancer cells, antiparasitics, enhancing
an
immune response, providing adjuvant activities or providing vaccine
activities, inhibiting
cancer metastasis or growth, reducing adhesion protein of cells, wherein the
adhesion
proteins comprise fibronectin, integrins family, Myosin, vitronectin,
collagen, laminin,
Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin,
CD 54,
CAM, elastin and FAK. In an embodiment, methods comprise inhibiting the gene
expression. In an embodiment, this invention provides a method of reducing the
secretion of fibronectin. In an embodiment the method can block the migration,
metastasis of cancer cells or inhibit the growth of cancers or anti-
angiogenesis, wherein
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the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian
cancer,
bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer,
leukemia
cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer,
cervix
cancer, esophagus cancer, testis cancer, spleen cancer, kidney cancer, lymph
cancer,
pancreas cancer, stomach cancer and thyroid cancer, In an embodiment the
compounds are anti-angiogenesis, inhibiting cancer cell metastasis and
inhibiting
cancer growth, In an embodiment the compounds promote angiopoietin 2 . In an
embodiment the compound is selected from the following formulas (1 E). In an
embodiment the method is administering contacting the compounds, wherein the
compound is selected from the formula (1 E):
R1a
R1
RA'16
411 RR 2
$
R13=-
R 50 R3
R9 R10 , also named (1 E), wherein
R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R4 represents CH3, CHO, CH2R6 or CORE, wherein R6 is selected from hydroxyl, 0-
angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl,
0-
alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted
phenyl, 0-
alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, 0-
alkenylcarbonyl and derivatives thereof; R3 is H or OH; R8 is H or OH,
particularly OH;
R16 is H or R4 and R16 may together form -CH2-X-, CH(OH)-X- or C(=O)-X-,
wherein the -X- may be 0 or N ; wherein when the C12-13 of ring 3 of the
triterpene
has a double bond then R16 is absent.
R5 is a hydrogen, heterocyclic or sugar moiety(ies), wherein the sugar
moiety(ies)
is/are selected from a group consisting of glucose, galactose, rhamnose,
arabinose,
xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose,
ribose, sorbose,
tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic
acid, and
derivatives or combination thereof; wherein R9, R10, R11, R12, R13, R14, R15
are
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33
independently attached a group selecting from CH3, CH2OH, CHO, COOH, COO-
alkyl,
COO-aryl, COO- heterocyclic, COO-heteroaryl, CH2Oaryl, CH2O- heterocyclic,
CH2O-
heteroaryl, alkyls group, hydroxyl, acetyl group, particularly CH3; wherein R4
and R16
form a divalent radical of formula CH2O, CH(OR7)O, or COOR7, wherein R7 is
hydrogen, alkyl, angeloyl, tigloyl, senecioyl, dibenzoyl, benzoyl, alkanoyl,
alkenoyl,
benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, and
derivatives
thereof; wherein at least two of R1, R2 and R6 are compriseing a group
selected from
O-angeloyl, O-tigloyl, O-senecioyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-
alkenoyl, 0-
benzoyl alkyl substituted O-alkanoyl, O-aryl, O-acyl, O-heterocylic, O-
heteroraryl, and
derivatives thereof; or at least one of R1, R2, and R4 is a sugar moiety
substituted with
at least two groups selected from a group consisting of angeloyl, acetyl,
tigloyl,
senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted
alkanoyl, aryl,
acyl, heterocylic, heteroraryl, and a derivative thereof; or wherein R4 is
CH2R6; wherein
R1 and R2 independently consists an O-angeloyl group, or at least two of R1,
R2 and
R6 are O-angeloyl or at least one of R1, R2 or R6 is a sugar moiety with two 0-
angeloyls; wherein R5 is/are the sugar moiety(ies) selected from the following
sugars
and alduronis acids: glucose, galactose, rhamnose, arabinose, xylose, fucose,
allose,
altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose,
talose,
fructose, glucuronic acid, galacturonic acid; or their derivatives thereof, or
the
combination thereof; wherein the sugar preferably comprises glucuronic acid,
arabinose
and galactose. In an embodiment, wherein R5 is/are sugar moiety(ies) selected
from a
group consisting of glucose, galactose, arabinose, alduronic acid, glucuronic
acid,
galacturonic acid, and a derivative or combination thereof. In an embodiment,
wherein
R5 is 3-{3-O-{[(a-L-rhamnopyranosyl-(1-*2)]-a-L-rhamnopyranosyl--(1 --->2)-[3-
D-
galactopyranosyl--(1 ->3)]-[(3-D- galactopyranosyl--(1 ->2)]- {3-D-
glucuronopyranosyl}. In
an embodiment, wherein the carbon ring 3 comprises a double bond when R16 is
H;
wherein the double bond in carbon ring 3 is reduced when R4 and R16 form a
divalent
radical.
In an embodiment the method is administering contacting the compounds, wherein
the
compound is selected from the formula (1 F):
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34
Ri R14
R4 R
O
R2
Rii Riz
R13=
R50 R3
Rg R10 , also named (1 F), wherein
R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, 0-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, 0-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
0-alkanoyl substituted phenyl, 0-alkenoyl substituted phenyl, 0-aryl, 0-acyl,
0-
heterocylic, O-heteroraryl, 0-alkenylcarbonyl and derivatives thereof;
R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, 0-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, 0-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, 0-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, 0-alkenylcarbonyl and derivatives thereof;
R4 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, 0-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, 0-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, 0-alkenoyl substituted phenyl, 0-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, 0-alkenylcarbonyl and derivatives thereof;
R3 is H or OH; R8 is H or OH, particularly OH;
R5 is a hydrogen or sugar moiety(ies), wherein the sugar moiety(ies) is/are
selected
from a group consisting of glucose, galactose, rhamnose, arabinose, xylose,
fucose,
allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose,
tagatose,
talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and
derivatives or
combination thereof; wherein R9, R10, R11, R12, R13, R14, R15 are
independently
attached a group selecting from CH3, CH2OH, CHO, COOH, COO-alkyl, COO-aryl,
COO-heterocyclic, COO-heteroaryl, CH2Oaryl, CH2O- heterocyclic, CH2O-
heteroaryl,
alkyls group, hydroxyl, acetyl group, particularly CH3; wherein at least two
of R1, R2 and
R4 are compriseing a group selected from 0-angeloyl, O-tigloyl, O-senecioyl, O-
dibenzoyl, O-benzoyl, 0-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-aryl, 0-acyl, O-heterocylic, O-heteroraryl, and derivatives thereof; or at
least one of
R1, R2, and R4 is a sugar moiety substituted with at least two groups selected
from a
group consisting of angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl,
alkanoyl,
alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic,
heteroraryl, and a
derivative thereof; or wherein R4, R1 and R2 independently consists an 0-
angeloyl
group, or at least two of R1, R2 and R4 are O-angeloyl or at least one of R1,
R2 or R4
is a sugar moiety with two O-angeloyls; wherein R5 is/are the sugar
moiety(ies)
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selected from the following sugars and alduronis acids: glucose, galactose,
rhamnose,
arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose,
psicose,
ribose, sorbose, tagatose, talose, fructose, glucuronic acid, galacturonic
acid; or their
derivatives thereof, or the combination thereof; wherein the sugar preferably
comprises
5 glucuronic acid, arabinose and galactose. In an embodiment,wherein R5 is/are
sugar
moiety(ies) selected from a group consisting of glucose, galactose, arabinose,
alduronic
acid, glucuronic acid, galacturonic acid, and a derivative or combination
thereof; In an
embodiment, wherein R5 is 3-3-0-{[(a-L-rhamnopyranosyl-(1 ->2)]-(x-L-
rhamnopyranosyl--(1 -2)-(3-D- galactopyranosyl--(1 -3)]-[(3-D-
galactopyranosyl--
10 (1 ->2)]- [3-D-glucuronopyranosyl}
In an embodiment the method is administering contacting the compounds of
following:
Ri R11
RRz
OH Re R, Rq
O O cc-F- Ri z õ'R3
HO
00
OH IoO R5
HO I~ R7 R,
O HO
CH3 rrOH yO
H
HO HO O O OH
CH3
OH
HO OH also named (1 G), wherein
R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, 0-
15 dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
20 O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-
acyl, 0-
heterocylic, O-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R4 represents CH3, CHO, CH2R6 or CORE, wherein R6 is selected from hydroxyl, 0-
angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl,
0-
alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted
phenyl, 0-
25 alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl,
0-
alkenylcarbonyl and derivatives thereof; R3 is H or OH; R5 is H or OH;
wherein R6, R7, R8, R9, R10, R11, R12 are independently attached a group
selecting
from CH3, CH2OH, CHO, COOH, COO-alkyl, COO-aryl, COO-heterocyclic, COO-
heteroaryl, CH2Oaryl, CH2O- heterocyclic, CH2O- heteroaryl, alkyls group,
hydroxyl,
30 acetyl group, particularly CH3;
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36
In an embodiment the method is administering contacting the compounds of
following:
R Rn
Rq R,
O
qz
OH Rs Re
HO 0 O COON Riz R3
OH 00 Rs
R' Rs
HO O 0 HO
CH3 OH o
HO 0
HO HO 0 O OH
CH3
HO OH OH also named (1 H), wherein
R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, 0-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, 0-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R4 is selected from hydroxyl, CH2OH, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, 0-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R3 is H or OH; R5 is H or OH; wherein R6, R7, R8, R9, R10, R11, R12 are
independently attached a group selecting from CH3, CH2OH, CHO, COOH, COO-
alkyl,
COO-aryl, COO- heterocyclic, COO-heteroaryl, CH2Oaryl, CH2O- heterocyclic,
CH2O-
heteroaryl, alkyls group, hydroxyl, acetyl group, particularly CH3;
In an embodiment the use or method is administering contacting the compounds
of
following:
R, R,
R,
Rz
RB R
a
O iz= RR3
u R13 R
00 5
OH
HO R7 RS
OH HO
OH C
HO 0
OH
OH
also named (1 J), wherein
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37
R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, 0-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-
alkyl, O-
dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-
alkanoyl,
O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl,
0-
heterocylic, O-heteroraryl, O-alkenylcarbonyl and derivatives thereof;
R4 represents CH3, CHO, CH2R6 or CORE, wherein R6 is selected from hydroxyl, 0-
angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl,
0-
alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted
phenyl, 0-
alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-
alkenylcarbonyl and derivatives thereof;
R3 is H or OH; R5 is H or OH, particularly OH; wherein R6, R7, R8, R9, R10,
R11, R12
are independently attached a group selecting from CH3, CH2OH, CHO, COOH, COO-
alkyl, COO-aryl, COO-heterocyclic, COO-heteroaryl, CH2Oaryl, CH2O-
heterocyclic,
CH2O- heteroaryl, alkyls group, hydroxyl, acetyl group, particularly CHs; R13
is COOH
or COO-alkyl,
R
Rz
OH Ry
O o COON R3
HO
OH QO R'
HO
C 0 HO
CH3 rrOH yC
HO 0
HO HO C O CH
CH3
HO OH OH ; also named (1 L) ,
wherein R1, R2 are angeloyl, R3 is OH, R4 is CH2OH, R5 is H or OH
In an embodiment the method is administering contacting the compounds of
following:
29
H3c
~DH
0-0
0
Ha0 H
21 CH20H
2 - DH
0 OH
OH O
HO
OH HO
O O
OH
OH or
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38
3-0-[3-D-galactopyranosyl(1 >2)] -3- D-xyopyranosyl (1 -3)-(3-D-
glucuronopyranosyl-
21-0-angeloyl, 22-O-angeloyl-3[3, 15a, 16a, 21[3, 22a, 28-hexahydroxyolean -12-
ene,
0
CH,OH \
OH
COOH 27 OH
O
O za z9
OH
HO HO
OH OH O
H O
OH
OH ,or
3-0-[[3-D-galactopyranosyl(1 ->2)]-[3- D-xyopyranosyl (1 ->3)-(3-D-
glucuronopyranosyl-21-
O-benzoyl, 22-O-benzoyl-3(3, 15a, 16a, 21[3, 22a, 28-hexahydroxyolean-1 2-ene
HOH3
H,~
cH,
21 HiOH O
OH
O COON -
OH O z¾ zs off
HO
OH HO
O
HO O
OH
OH ,or
3-0-[(3-D-galactopyranosyl(1 ->2)]-[3- D-xyopyranosyl (1 -3)-3-D-
glucuronopyranosyl-21-
O-(2-m ethyl pro panoyl)-O-angeloyl, 22-0-(2- methylbutanoyl) -3(3, 15a, 16a,
213, 22a,
28-hexahydroxyolean-1 2-ene,
A sugar moiety is a segment of a molecule comprising one or more sugar groups.
Substitution, deletion and/or addition of any group in the above-described
compounds
will be apparent to one of ordinary skill in the art based on the teaching of
this
application. In a further embodiment, the substitution, deletion and/or
addition of the
group(s) in the compound of the invention does not substantially affect the
biological
function of the compound.
A method or a use of compound for manufacture of medicament of inhibiting
venous
insufficiency, particularly hemorrhoids or inhibiting leg swelling, or
peripheral edema,
antilipemic, chronic venous disease, varicose vein disease, varicose syndrome,
venous
stasis, Expectorant, peripheral vascular disorders, cerebro-organic
convulsion, cerebral
circulation disorder, cerebral edema, psychoses, dysmenorrheal, hemorrhoids,
episiotomies, hamonhoids, peripheral edema formation or postoperative
swelling; for
reducing symptoms of pain; for reducing symptoms of stomach pain; for reducing
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39
symptoms of leg pain; for treating pruritis, lower leg volume, thrombosis,
thromophlebitis;
for preventing gastric ulcers antispasmotic comprising administering to a
subject, in
need thereof, an effective amount of the composition of any one of the above
compounds or a compound comprises a triterpene which comprises any two of
angeloyl, tigloyl, senecioyl, perferable two angeloyl groups, and a sugar
moiety,
glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose,
gulose, idose,
lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose,
alduronic acid,
glucuronic acid or galacturonic acid, or a derivative thereof, or the
combination thereof,
preferable selected from glucuronic acid, galacturonic acid, glucose,
galactose and
arabinose. The method is regulating or interacting with adhesion protien,
wherein the
adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin,
collagen,
laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin,
tenascin,
CD 54, CAM, elastin and FAK. In an embodiment, the method is reducing the
secretion
of fibronectin. In an embodiment, the method comprises inhibiting
leishmaniases,
modulating adhesion or angiogenesis of cancer cells, antiparasitics or
manufacturing an
adjuvant composition. In an embodiment, antiparasitics comprise inhibiting
leishmaniases, amoebiasis, trypanosomiasis, toxoplasmosis or malaria.
This invention provides a method for inhibiting the growth, migration,
metastasis of
cancer by altering the characteristic of membrane of cancer cell, wherein the
characteristic comprise reducing adhesion protein; wherein the adhesion
proteins
comprise fibronectin, integrins family, Myosin, vitronectin, collagen,
laminin,
Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin,
CD 54,
CAM, elastin and FAK; wherein comprising inhibiting the secretion of
fibronectin,
wherein comprising administering to a subject, in need thereof, an appropriate
amount
of triterpenoidal saponins comprising two or more angeloyl groups, or a
compound
comprises a triterpene which comprises any two of angeloyl, tigloyl,
senecioyl,
perferable two angeloyl groups, and a sugar moiety, glucose, galactose,
rhamnose,
arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose,
psicose,
ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid
or
galacturonic acid, or a derivative thereof, or the combination thereof,
preferably selected
from glucuronic acid, galacturonic acid, glucose, galactose and arabinose.
This
invention provides a composition comprising an effective amount of the
compound of
any one of compound selected from the above formula or a salt, ester,
metabolite or
derivative thereof as a medicament for reducing adhesion protein; wherein the
adhesion
proteins comprise fibronectin, integrins family, Myosin , vitronectin,
collagen, laminin,
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Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin,
CD 54,
CAM, elastin and FAK, for inhibiting the growth, migration, metastasis of
cancer,
wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer,
ovarian
cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain
cancer,
5 leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer,
renal
cancer or cervix cancer.
This invention also provides a composition comprising the above described
compounds
or their derivatives for reducing adhesion protein, wherein the adhesion
proteins
10 comprise fibronectin, integrins family, Myosin, vitronectin, collagen,
laminin,
Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin,
CD 54,
CAM, elastin and FAK; wherein comprising inhibiting the secretion of
fibronectin,
wherein for treating venous insufficiency, particularly hemorrhoids or
inhibiting leg
swelling, or peripheral edema, antilipemic, chronic venous disease, varicose
vein
15 disease, varicose syndrome, venous stasis, Expectorant, peripheral vascular
disorders,
cerebro-organic convulsion, cerebral circulation disorder, cerebral edema,
psychoses,
dysmenorrheal, episiotomies, hemonhoids, peripheral edema formation or
postoperative
swelling; for reducing symptoms of pain; for reducing symptoms of stomach
pain; for
reducing symptoms of leg pain; for treating pruritis, lower leg volume,
thrombosis,
20 thromophlebitis; for preventing gastric ulcers antispasmotic, inhibiting
leishmaniases ,
for modulating adhesion or angiogenesis of cancer cells, antiparasitics or
manufacturing
an adjuvant composition. In an embodiment of the above, the uses of
compositions
comprising any one of triterpenoid saponins with the following formula:
3-0-{[/3-D-galactopyranosyl (1-2)]-[a-L-arabinofuranosyl (1-3)]-,Q D-
25 glucuronopyranoside butyl ester}-21-O-acetyl-22-O-angeloyl-
3/3,16a,21,6,22a,28-
pentahydroxyolean-12-ene.
3-0-[{3-D-galactopyranosyl(1 -2)]-a-L-arabinofuranosyl(1 ->3)-(3-D-
glucuronopyranosyl-
21,22-O-diangeloyl-3(3, 15a, 16x, 21{3, 22a, 28-hexahydroxyolean-12-ene,
3-0-[R-D-galactopyranosyl(1 ->2)]-a-L-arabinofuranosyl(1 -3)-(3-D-
glucuronopyranosyl -
30 21-0-(3,4-diangeloyl)-a-L-rhamnophyranosyl-22-O-acetyl-3(3,16a, 21{3, 22a,
28-
pentahydroxyolean-1 2-ene,
3-0-[3-D-glucopyranosyl-(1 -2)]-a-L-arabinofuranosyl(1 -3)-(3-D-
glucuronopyranosyl-
21,22-O-diangeloyl-3{3, 15a, 16a, 21 {3, 22a, 24[3, 28-heptahydroxyolean-1 2-
ene,
3-0-[,8-glucopyranosyl (1 -2)]-a-arabinofuranosyl (1 -3)-,6-glucuronopyranosyl-
21, 22-
35 O-diangeloyl-3,6, 16a, 21,6, 22a, 24,6, 28-hexahydroxyolean-12-ene,
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41
3-0-[,(3-galactopyranosyl (1->2)]-a-arabinofuranosyl (1-3)-,6-
glucuronopyranosyl-21-0-
(3,4-diangeloyl)-a-rhamnopyranosyl-28-0-acetyl-3,(3, 16a, 21,6, 22 a, 28-
pentahydroxyolean-1 2-ene,
3-0-[,6-galactopyranosyl (1 ->2)]-a-arabinofuranosyl (1 ->3)-,Q
glucuronopyranosyl-21,
22-O-diangeloyl-3/3, 16a, 21,6, 22a, 28-pentahydroxyolean-12-ene,
3-0-[ 3-D-galactopyranosyl(1->2)]-a-L-arabinofuranosyl(1-3)-(3-D-
glucuronopyranosy I-
21 -0-angeloyl, 22-0-(2-m ethyl propanoyl)-3(3, 15a, 16a, 21 [3, 22a, 28-
hexahydroxyolean-1 2-ene,
3-0-[(3-D-galactopyranosyl-(1 -2)]-a-L-arabinofuranosyl-(1 -3)-/3-D-
-glucuronopyranosyl-21-0-angeloyl-28-0-2-methylbutanoyl-3/3, 15 a, 16a, 21/3,
22a, 28-
hexahydroxyolean-1 2-ene
This invention also provides a composition for regulating or reducing adhesion
protein,
wherein the adhesion protein comprising fibronectin, integrins family, CD44,
Myosin VI,
vitronectin collagen, laminin, Glycosylation cell surface proteins,
polyglycans and FAK;
inhibiting venous insufficiency, particularly hemorrhoids or inhibition of leg
swelling, or
inhibiting cancer growth, inhibiting leishmaniases, modulating adhesion of
cancer cells,
modulating angiogenesis of cancer cells, antiparasitics or manufacturing an
adjuvant
composition, comprising any of compounds selected from the following compounds
(A)
to (X) and (Al) to (X1) incorporated here from PCT/US2008/002086, 1188-ALA-
PCT,:
In an embodiment, a triterpene comprise the following structure has activities
of
reducing adhesion proteins to blocks the migration, metastasis of cancer
cells, growth of
cancers, inhibiting leishmaniases, modulating adhesion or angiogenesis of
cancer
cells, antiparasitics, or manufacturing an adjuvant composition.
OR,
OR,
R50 (e)
wherein at least two of R1, R2 and R3 comprise compounds selected from
angeloyl,
acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl
alkyl
substituted alkanoyl, aryl, heterocylic, heteroraryl, alkanoyl substituted
phenyl, alkenoyl
substituted phenyl, alkenylcarbonyl or substituted with an C2-9 acid or
derivative thereof.
In an embodiment, at least one of R1, R2 and R3 comprise a sugar moiety
comprising
two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl,
benzoyl,
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dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl,
heterocylic,
heteroraryl, alkanoyl substituted phenyl, alkenoyl substituted phenyl,
alkenylcarbonyl or
substituted with an C2-9 acid or derivative thereof. In embodiment, R1, R2 or
R3
comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or
their
combinations, preferable wherein at least two of the R1, R2 and R3 comprise
angeloyl
groups. In an embodiment, R5 comprises sugar moiety. In an embodiment, the
sugar
moiety comprises at least one sugar, or glucose, or galactose, or rhamnose, or
arabinose, or xylose, or alduronic acid, or glucuronic acid, or galacturonic
acid, or their
derivative thereof, or the combination thereof. In an embodiment, the sugar
moiety
comprises one or more sugar selected from, but is not limited to glucose,
galactose,
rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose,
mannose,
psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid,
glucuronic acid,
galacturonic acid, or derivatives thereof, or the combination thereof. In an
embodiment,
the sugar moiety comprise glucose, galactose or arabinose, or combination
thereof, or
derivatives thereof. In an embodiment, the sugar moietiy comprise alduronic
acids,
galactose and arabinose, wherein the alduronic comprise glucuronic acid or
galacturonic acid. In an embodiment, the sugar moiety comprise alduronic
acids,
glucose and arabinose, wherein the alduronic comprise glucuronic acid or
galacturonic
acid. In an embodiment, R5 is Hydrogen. In an embodiment, the R1, R 2 and R3
may
be attached in other position of the structure.
In an embodiment, the compound is triterpenoid saponin comprise comprises at
least
two angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their
combinations, preferable wherein at least two angeloyl groups.
In an embodiment, at least two compounds selected from angeloyl, acetyl,
tigloyl,
senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted
alkanoyl, aryl,
acyl, heterocylic, heteroraryl, alkanoyl substituted phenyl, alkenoyl
substituted phenyl,
alkenylcarbonyl or substituted with an C2-9 acid or derivative thereof.
In an embodiment, at least one of the side bonds comprise a sugar moiety
comprising
two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl,
dibenzoyl,
alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl,
heterocylic, heteroraryl,
alkanoyl substituted phenyl, alkenoyl substituted phenyl, alkenylcarbonyl or
substituted
with an C2-9 acid or derivative thereof.
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In an embodiment, the compound comprises a sugar moiety. In a further
embodiment,
the sugar moiety comprises glucose, galactose or arabinose or combination
thereof.
In a further embodiment, the sugar moiety comprises at least one sugar, or
glucose, or
galactose, or rhamnose, or arabinose, or xylose, or alduronic acid, or
glucuronic acid, or
galacturonic acid, or their derivative thereof, or the combination thereof.
In a further embodiment, the sugar moiety comprises one or more sugar selected
from,
but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose,
allose,
altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose,
talose,
fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives
thereof, or the
combination thereof.
A composition comprising an effective amount of compound selected from the
above
formula or a salt, ester, metabolite or derivative thereof as a medicament for
regulating
or reducing adhesion protein, blocking the migration, metastasis of cancer
cells,
inhibiting tumor or cancer cell growth and for treating cancer, wherein the
cancers
comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone,
brain, leukemia,
lung, colon, CNS, melanoma, renal and cervix cancer.
In a further embodiment, a compound or sapongenin comprises the structure (d)
or (e)
has anti-cancer or inhibiting virus activities.
A composition for regulating or reducing adhesion protein, blocking the
migration,
metastasis of cancer cells, treating cancers or inhibiting virus, comprising a
compound,
wherein the compound is a triterpene, which comprises at least two side chains
which
comprise angeloyl groups, wherein the side chains are at adjacent carbon in
trans
position. In an embodiment, the side chains are at alternate carbon in cis
position. In an
embodiment, the side chains are at alternate carbon in trans position. In an
embodiment,
the side chains are attached an acyl. In an embodiment, the side chains are
attached an
unsaturated group.
In an embodiment, the side chains are in non-adjacent carbon cis or trans
position. In
an embodiment, the side chains comprise a functional group capable of
performing the
function of angeloyl group.
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The above compounds can be used for regulating or reducing adhesion protein,
blocking the migration, metastasis of cancer cells, inhibiting tumor cell
growth, reducing
leg swelling, symptoms of chronic venous insufficiency, peripheral edema,
antilipemic,
chronic venous disease, varicose vein disease, varicose syndrome, venous
stasis,
expectorant, peripheral vascular disorders, by administering to a subject in
need
thereof, an effective amount of the above described compounds.
This invention provides a method for inhibiting tumor cell growth, regulating
cell growth,
reducing inflammation, inhibiting leishmaniases, modulating adhesion or
angiogenesis
of cancer cells, antiparasitics or manufacturing an adjuvant composition,
comprising
administering to a subject, in need thereof, an effective amount of the
compound which
comprises any of the above structures to said subject. The cancers are
included but not
limited to Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma
cancer,
Ovarian cancer, Renal cancer, Prostate cancer, Breast cancer, bladder cancer,
cervix
cancer, liver cancer, bone cancer, brain cancer and Skin cancer.
This invention also provides a method for reducing swelling, reducing symptoms
of
chronic venous insufficiency, peripheral edema, antilipemic, chronic venous
disease,
varicose vein disease, varicose syndrome, venous stasis, Expectorant,
peripheral
vascular disorders, cerebro-organic convulsion, cerebral circulation disorder,
cerebral
edema, psychoses, dysmenorrheal, hemorrhoids, episiotomies, peripheral edema
formation or postoperative swelling; for reducing symptoms of leg pain; for
treating
pruritis, lower leg volume, for reducing symptoms of pain; thrombosis,
thromophlebitis;
for preventing gastric ulcers antispasmotic, comprising administering to a
subject, in
need thereof, an effective amount of the composition of this invention.
This invention provides a composition comprising the compounds provided in the
invention for treating cancers; for inhibiting virus; for preventing cerebral
aging; for
improving memory; improving cerebral functions, for curing enuresis, frequent
micturition, urinary incontinence,dementia, Alzheimer's disease, autism, brain
trauma,
Parkinson's disease or other diseases caused by cerebral dysfunctions; for
treating
arthritis, rheumatism, poor circulation, arteriosclerosis, Raynaud's syndrome,
angina
pectoris, cardiac disorder, coronary heart disease, headache, dizziness,
kidney
disorder; cerebrovascular diseasea; inhibiting NF-Kappa B activation; for
treating brain
edema, sever acute respiratory syndrome, respiratory viral diseases, chronic
venous
insufficiency, hypertension, chronic venous disease, anti-oedematous, anti
inflammatory,
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hemonhoids, peripheral edema formation, varicose vein disease, flu, post
traumatic
edema and postoperative swelling;for inhibiting blood clot, for inhibiting
ethanol
absorption; for lowering blood sugar; for regulating the adrenocorticotropin
and
corticosterone level. This invention provides a composition for AntiMS,
antianeurysm,
5 antiasthmatic, antibradykinic, anticapillarihemorrhagic, anticephalagic,
anticervicobrachialgic, antieclamptic, antiedemic, antiencaphalitic,
antiepiglottitic,
antiexudative, antiflu, antifracture, antigingivitic, antihematomic,
antiherpetic,
antihistaminic, antihydrathritic, antimeningitic, antioxidant,
antiperiodontic, antiphlebitic,
antipleuritic, antiraucedo, antirhinitic, antitonsilitic, antiulcer,
antivaricose, antivertiginous,
10 cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic,
hyaluronidase inhibitor,
lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic,
vasoprotective,
inhibiting leishmaniases, modulating adhesion or angiogenesis of cancer
cells, antiparasitics, or manufacturing an adjuvant composition and venotonic
treatment.
15 Alkenyl means unsaturated linear or branched structures and combinations
thereof,
having 1-7 carbon atoms, one or more double bonds therein. Non-limiting
examples of
alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, s- and t-
butenyl, pentenyl,
hexenyl, butadienyl, pentadienyl, and hexadienyl.
20 An aryl is a functional group of organic molecule derived from an aromatic
compound
such as benzene, a 6-14 membered carbocyclic aromatic ring system cpmprising 1-
3
benzene rings. If two or more aromatic rings are present, then the rings are
fused
together, so that adjacent rings share a common bond. Examples include phenyl
and
naphthyl. The aryl group may be substituted with one or more sunstitutes
independnetly
25 selected from halogen, alkyl or alkoxy.
Acyl is a functional group obtained from an organic acid by the removal of the
carboxyl.
Acyl groups can be written as having the general formula -COR, where there is
a double
bond between the carbon and oxygen. The names of acyl groups typically end in -
yl,
30 such as formyl, acetyl, propionyl, butyryl and benzoyl.
Benzoyl is one of acyls, C6H5COR, obtained from benzoic acid by the removal of
the
carboxyl.
Heterocyclic compound - a compound containing a heterocyclic ring which refers
to a
35 non-aromatic ring having 1-4 heteroatoms said ring being isolated or fused
to a second
ring selected from 3- to 7-membered alicyclic ring containing 0-4 heteroatoms,
aryl and
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heteroaryl , wherein said heterocyclic comprises pyrrolidinyl , pipyrazinyl
morpholinyl, trahydrofuranyl, imidazolinyl, thiomorpholinyl, and the like.
Heterocyclyl groups derived from heteroarenes by removal of a hydrogen atom
from
any ring atom.
Alkanoyl is the general name for an organic functional group RCO-, where R
represents
hydrogen or an alkyl group. Preferably alkanoyl is selected from acetyl,
propionoyl,
butyryl, isobutyryl, pentanoyl and hexanoyl.
Alkenoyl is alkenylcarbonyl in which alkenyl is defined above. Examples are
pentenoyl(tigloyl) and hexenoyl(angeloyl).
Alkyl is a radical containing only carbon and hydrogen atoms arranged in a
chain,
branched, cyclic or bicyclic structure or their combinations, having 1-18
carbon atoms.
Examples include but are not limited to methyl, ethyl, propyl isopropyl,
butyl, s- and t-
butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl,
tetradecyl,
pentadecyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Benzoyl alkyl substituted alkanoyl is refer to straight or branched C1-C6
alkanoyl
substituted with at least one benzoyl and at least one alkyl, wherein the
benzoyl is
attached to a straight or branched C1-C6 alkyl. Preferably a benzoyl alkyl
substituted
alkanoyl is benzoyl methyl isobutanoyl.
A sugar moiety is a segment of molecule comprising one or more sugars or
derivatives
thereof or alduronic acid thereof.
Isobutyryl is Synonym of 2-Methylpropanoyl
Y and Y3 represent the same compound.
YM and (ACH-Y) represent the same compound.
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0
(Z)-O(C=O)C(CH3)=CH-C6H5 is [O-
C5 alkenoyl substituted with phenyl]
H3C
0
(Z)-O(C=O)CH=CH-C6H5 is [0-C4
alkenoyl substituted with phenyl]
0
(E)-O(C=O)CH=CH-C6H5 is [0-C4
alkenoyl substituted with phenyl]
0
O(C=O)C6H5, Benzoyl is [0-C2
alkanoyl substituted with phenyl]
0
(2Z)-2-methyl-3-phenylacrylic acid HO
H3
0
(2Z)-3-phenylacrylic acid H0
0
(2E)-3-phenylacrylic acid Ho
0
Benzoic acid HO
H3C
O-Angeloyl: -0- i cH3
O(C=O)C(CH3)=CH(CH3) 0
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This invention provides a method of altering the characteristic of cancer cell
membrane
to block the migration, metastasis of cancer cells or inhibit the growth of
cancers or anti-
angiogenesis.
This invention provides a composition and method for inhibiting the growth,
migration,
metastasis of cancer by altering the adhesion characteristic of membrane of
cancer cell,
wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer,
ovarian
cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain
cancer,
leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal
cancer or cervix cancer, wherein the method is administering contacting
Xanifolia Y0,
Y1, Y2, Y, Y5, Y7, Y8, Y9, Y10, or a salt, ester, metabolite thereof. In an
embodiment
the method is administering contacting the compound selected from formula in
this
application.
This application shows Xanifolia-Y is an alternate or supplemental agent to
DNA-
inhibition or microtubule-targeting drugs. It could be beneficial if it is
used singly or in
combination with other drugs of different mechanisms (block M-phase
progression or
DNA synthesis). Our inventions show combined effect of Xanifolia-Y and
paclitaxel on
inhibition of ES2 cells' growth (Detail in Experiment 14 U.S. Serial Nos.1 1
/6831 98, filed
on March 7, 2007) .
Identify the binding target of Xanifolia-Y of adhesion proteins and signaling
proteins in
ovarian cancer cells.
In our animal studies, it was shown that Xanifolia-Y extended the life span of
tumor
bearing mice. (Reference Experiments 7, 8, 9 in U.S. Serial Nos.1 1 /6831 98,
filed on
March 7, 2007,). The animals died sooner if the treatment of Xanifolia-Y was
delayed
(comparing results of treatments started from 1, 4 or 10 days after tumor
inoculation).
The results show that Xanifolia-Y inhibits migration or metastasis of the
inoculated
cancer cells. Ovarian carcinoma cells express high levels of adhesion
molecules.
Adhesion proteins are present in both cancer cells and mesothelial cells.
While the lost
of adhesion blocks of the protein accessibility due to a result of modulating
by Xanifolia-
Y, In an embodiment, the interaction of Xanifolia-Y with membrane alter the
adhesion
protein's binding site(s).
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Fibronectin is a kind of glycoprotein that binds to membrane spanning receptor
proteins
comprising the integrins, collagen, fibrin and heparin sulfate. Fibronectin
has been
implicated in tumor development and metastasis. This application provides
methods
and compositions for modulating the gene expression of fibronectin, inhibiting
the
secretion of fibronectin, reducing the receptors of fibronectin, reducing the
adhesion
ability fibronectin, inhibiting the metastasis, or inhibiting cancer growth,
wherein the
method and composition comprises administering to the said subject as
effective
amount of compounds selected in this appliaction.
Angiogenesis is a process involving the growth of new blood vessels. It is a
normal
process in growth and development. However, this is also a fundamental step in
the
transition of tumors from a dormant state to a malignant state. The
angiopoietins are
protein growth factors that modulate angiogenesis. The identified
angiopoietins
comprise angiopoietin 1, angiopoietin 2, angiopoietin 3, angiopoietin 4,
angiopoietin 5,
angiopoietin 6, angiopoietin 7, angiopoietin-like 1, angiopoietin-like 2,
angiopoietin-like 3,
angiopoietin-like 4, angiopoietin-like 5, angiopoietin-like 6, and
angiopoietin-like 7. In an
embodiment, the angiopoietin 1 is a positive foctor to promote the new blood
vessels. In
embodiment, the angiopoietin 2 is antagonist of angiopoietin 1, which is a
negative
factor for the growth of new blood vessels. This application provides methods
and
compositions for modulating angiopoietin and inhibiting cancer growth; wherein
the
cancers comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin,
bone, brain,
leukemia, lung, colon, CNS, melanoma, renal and cervix cancer, wherein the
methods
and compositions comprise administering to the said subject as effective
amount of
compounds selected in this appliaction. The compounds in this application are
positive
regulating angiopoietin 2. The compounds in this application are negative
regulating the
angiopoietin 1. The results of the micro array experiment showed that compound
Y and
YM (ACH-Y) modulate the gene expression of angiopoietin family in ES2 cells.
They
promote angiopoietin 2 and inhibit angiopoietin 1 and angiopoietin-like 1 and
angiopoietin-like 4.
The compounds in this application are used antiparasitics, enhancing an immune
response, providing adjuvant activities or providing vaccine activities, anti-
angiogenesis,
inhibiting cancer cell metastasis and inhibiting cancer growth, wherein the
compounds
comprise Xanifolia Y0, Y1, Y2, Y, Y7, Y8, Y9, Y10, ACH-Y or a salt, ester,
metabolite
thereof and compounds selected from formula (1 A), (1 B), (1 C) , (1 D), (1
E), (1 F), (1 G),
(1 H), (1 J), (1 K), (1 L). In an embodiment the method is administering
contacting the
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compound in this application comprising Xanifolia Y0, Y1, Y2, Y, Y7, Y8, Y9,
Y10,
Xanifolia (x), Escin or Aescin or a salt, ester, metabolite thereof. In an
embodiment the
compound may be selected from formulas (1 A), (1 B), (1 C), (1 D) (1 E), (1
F), (1 G), (1 H),
(1 J), (1 K), (1 L). In an embodiment, the compound comprises a triterpene
backbone, two
5 angeloyl groups and sugar moiety. In an embodiment the compound(s) are
selected
from Compound A to X and Al to X1 in the application. In an embodiment the
compound(s) are selected from Compound Z1 to Z7 in the application. In an
embodiment the compound(s) are selected from ACH-Z4, ACH-Y10, ACH-Y2, ACH-Y8,
ACH-Y7, ACH-Y0, ACH-X, ACH-E. In an embodiment the saponins comprise Bat, Ba2,
10 Ba3, Ba4, Bas, Ba6, Ba7, Bab, Ba9, Bal 0, Ball 1, Ball 2, Ball 3, Ball 4,
Ball 5, Ball 6, Ba
17.
The triterpene compounds of this invention can be administered to a subject in
need
thereof treating the subject, wherein including preventing canceror has
adjuvant effect
15 to the subject, or inhibiting the initation or promotion of cancer, or
killing the
cancer/tumor cells. In an embodiment the compounds inhibit the activation of
nuclear
factor-kB, wherein inhibiting the localization or wherein binding the DNA. In
an
embodiment the compounds induce apoptosis in cancer cells.
The triterpene compounds of this invention can reduce blood vessel in the
tumor in a
20 subject. (Figure 1)
Table 1 to 12, Effect of Y and YM on gene expression (Table of 1 to 12
PCT/US2008/002086, 1188-ALA-PCT, filed February 15, 2008 are incorporated
herein by reference )
Table 13: Effects of Y and YM on Glypican expression in ES2 cells
Probe Set ID Y/D Ym/D Gene.Symbol Gene.Title
243865 x at -2.7 -2.0 GPC6 Glypican 6
227059_at -2.2 -1.8 GPC6 Glypican 6
The results of the micro array experiment showed that compound Y and Ym
inhibit gene
expression of Glypican in ES2 cells.
Table 14: Effects of Y and YM on regulator of G-protein expression in ES2
cells
Probe Set ID Y/D Ym/D Gene.Symbol Gene.Title
204339 s at -3.5 -1.2 RGS4 regulator of G -protein signalling 4
204337 at -3.4 -1.1 RGS4 regulator of G -protein signalling 4
204338 s at -2.5 -1.1 RGS4 regulator of G -protein signalling 4
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The results of the micro array experiment showed that compound Y and YM
inhibit gene
expression of G-protein in ES2 cells
Table 15: Effects of Y and YM on thrombospondin in ES2 cells
Probe Set ID Y/D Ym/D Gene.Symbol Gene.Title
201109 s at -2.0 -6.2 THBS1 thrombospondin 1
201110 s at -1.8 -4.5 THBS1 thrombospondin 1
201108_s_at -1.7 -2.2 THBS1 thrombospondin 1
The results of the micro array experiment showed that compound Y and YM
inhibit gene
expression of thrombospondin in ES2 cells
Table 16: Effects of Y and YM on insulin-like growth factor binding protein
expression
in ES2 cells
Probe Set ID Y/D YM/D Gene.Symbol Gene.Title
insulin-like growth factor binding protein
210095_s_at -4.0 -3.5 IGFBP3 3
insulin-like growth factor binding protein
212143_s_at -3.7 -5.3 IGFBP3 3
insulin-like growth factor binding protein
201508_at -1.7 -2.4 IGFBP4 4
insulin-like growth factor binding protein
205302_at -1.7 -1.8 I G F B P 1 1
insulin-like growth factor binding protein
201163_s_at -1.4 -2.7 IGFBP7 7
insulin-like growth factor binding protein
203851_at -1.3 -1.8 IGFBP6 6
The results of the micro array experiment showed that compound Y and YM
inhibit gene
expression of insulin-like growth factor binding protein in ES2 cells.
Table 17: Effects of Y and YM on RAB3B, member RAS oncogene family protein
expression in ES2 cells
ID Y/D YM/D Gene.Symbol Gene.Title
242629_at -3.5 -1.8 RAB3B RAB3B, member RAS oncogene family
205924_at -1.7 -1.8 RAB3B RAB3B, member RAS oncogene family
227123_at -1.6 -1.2 RAB3B RAB3B, member RAS oncogene family
205925_s_at -1.2 -1.2 RAB3B RAB3B, member RAS oncogene family
The results of the micro array experiment showed that compound Y and Ym
inhibit gene
expression of RAB3B, member RAS oncogene family protein in ES2 cells.
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Table 18: Effects of Y and YM on potassium channel, subfamily U, protein
expression
in ES2 cells
ID Y/D YM/D Gene.S mbol Gene.Title
potassium channel,
237273_at -4.0 -1.9 KCNU1 subfamily U, member 1
The results of the micro array experiment showed that compound Y and Ym
inhibit gene
expression of family protein relate to potassium channel in ES2 cells.
protein phosphatase 1, regulatory
37028_at 2.4 5.6 PPP1R15A (inhibitor) subunit 15A
protein phosphatase 1, regulatory
202014 at 2.6 6.2 PPP1R15A (inhibitor) subunit 15A
215501 sat 3.2 7.1 DUSP10 dual specificity phosphatase 10
221563 at 3.8 5.7 DUSP10 dual specificity phosphatase 10
Fibronectin secretion studies summary:
Reduction of Fibronectin secretion from ES2 cells after xanifolia-Y treatment.
(Results of F1, F3, F4, F5, F7, F8, F11, F12A, F15, F16, F17) Data in
PCT/US2008/002086, 1188-ALA-PCT, filed February 15, 2008 are incorporated
herein
by reference
(Fl 1) For lung carcinoma cells (H460), at concentration of 20ug/ml, there are
inhibitions
of Fibronectin secretion ranged from 20-60%.
(F12A) For bladder carcinoma cells (HTB-9), Xanifolia-Y (10 ug/ml) inhibits
50% of
Fibronectin secretion.
(F15) In liver HepG2 cells. 10 ug/ml of xanifolia-Y inhibits 42% secretion of
Fibronectin.
(F16) Incubation of brain glioblastoma T98G cells withl0ug/ml of xanifolia-Y
inhibits
27% Fibronectin secretion and with 20ug/ml Y inhibits74% Fibronectin
secretion.
(F17) For skin SK-Mel-5 cells, the inhibition is 40-57% with 20 ug/ml of
Xanifolia-Y.
Studies of xanifolia-Y analogs and other saponin on Fibronectin secretion from
ES2 cells. Results of (F 23, F21, F 13, F14, F24, F25, 26, 31 B, F27,29, F28,
30, F 31,
32, F 33, F20) in PCT/US2008/002086, 1188-ALA-PCT, filed February 15, 2008)
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ES2 cells R-ES- X-10 Y0-10 Y1-10 Y3-10 Y7-10 ACH-Y- AKOH-80
20
%inhibition 19 39 34 41 47 34 48 No effect
Studies of other saponins on Fibronectin secretion from ES2 and other cells
ES2 cells Mb12-10 Mb5-10 ACH-Mb5-10 Bat -10 Ba4-10 AKOH-Mb-40
%inhibition 30 35 30 30 28 No effect
Liver
HepG2 Mb12-10 Mb5-10 ACH-Mb5-10 Bat -10 Ba4-10
%inhibition 30 35 25 33 28
5
Lung
H460 Mb12-10 Mb5-10 ACH-Mb5-10 Bat -10 Ba4-10
%inhibition 20 25 22 19 18
Bladder
HTB-9 Mb12-10 Mb5-10 ACH-Mb5-10 Bat -10 Ba4-10
% inhibition 32 28 30 25 30
Brain
T98G Mb12-10 Mb5-10 ACH-Mb5-10 Bat -10 Ba4-10
% inhibition 40 33 35 26 24
Skin
SK-MEL-5 Mb12-10 Mb5-10 ACH-Mb5-10 Bat-10 Ba4-10
% inhibition 17 15 20 10 10
Up regulation of Angiopoietin 2 (Ang2) in ES2 cells with Xanifolia-Y
treatment.
The results of study in PCT/US2008/002086, 1188-ALA-PCT, filed February 15,
2008
are incorporated herein by reference.
Data obtained from our Microarray experiments disclose that Xanifolia Y
modulates
gene expression of the following genes (represented by gene symbol):
Gene Symbol: ABL2, ADAMTS1, AKR1C3, AMIGO2, ANGPT2, ANKRD11, AP2B1,
APEH, APLP2, ARL10C, ARMC4, ARMCX1, ARMCX6, ARNTL2, ARNTL2, ATF3,
ATP6VOE, ATP6V1 B2, ATP6V1 C1, ATP6V1 C1, BCL2A1, BCL6, BR13, BTD,
C14orf109, C14orf78, C17orf32, C6orf65,C9orf10, C9orf103, CAD, CAV1, CAV2,
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CBLL1, CCL20, CD33L3, CEBPB, CEP4, CFH /// CFHL1, CHRDL1, CITED2, CITED2,
CLDN14, CLN8, CLTA, CNAP1, COG6, COL18A1, COL4A2, COL5A1, COL5A2,
COL6A3, COPG, CPM, CPNE3, CPSF1, CSRP2BP, CSTB, CTNS, CXCL2, DDB1,
DDIT3, DDX20, DKFZP56411171, DKFZP586JO619, DUSP10, DUSP10, DYRK3,
EEF2K, EFEMP1, EMP1, EVC, EV12A, EXT2, FAM62A, FER1L3, FLJ14466, FLNA,
FN1, FN1, GANAB, GDF15, GEM, GNPDA1, GPAA1, GPC6, GPNMB, GPNMB, GUSB,
H2AFV, H2AFV, HDAC9, HDLBP, HECW2, HMGA2, HMOX1, HSDL2, HSPBAP1,
HSPC196, HYOU1, IDS, IGFBP3, IKBKAP, INSIG1, IPO4, IRS2, JAG1, KDELR3,
KIAA0251, KIAA0586, KIAA1211, KIAA1462, KIAA1706, KIAA1754, KRT18, KRT7,
KRTAP4-7, LAMP2, LEPR, LEPREL1, LHFPL2, LIF, LOC286044, LOC339229,
LOC90693, LRRC8E, MAFG, MAGED2, MCTP1, MGC16291, MGC19764, MGC5618,
MRPS30, MRPS31, MTERFD3, MYH9, NAGA, NAV2, NCSTN, NEK9, NEW, NFKBIZ,
NMT2, NPC2, NSUN5C, NTNG1, NUP188, OACT2, OS9, P4HA1, P8, PALM2-AKAP2,
PALM2-AKAP2, PARVA, PBX2, PDE4DIP, PDIA4, PDIA6, PEG10, PHF19, PIK4CA,
PLEKHM1, PLOD1, PLOD2, PPP1R15A, PPP1R15A, PRKDC, PRSS23, PRSS23,
PSEN2, PSMD1, PTPRF, PTPRJ, RAB32, RAB9A, RG9MTD1, RGS4, RHOQ, RND3,
RNF25, RNPEP /// UBE2V1 /// Kua /// Kua-UEV, RNU17D, ROBO4, RRAGC, RRS1,
SEC31 L1, SERPINB2, SERPINB7, SESN2, SGEF, SGSH, SKIV2L, SLC25A21,
SLC35A3, SLC3A2, SMARCA1, SNAPC1, SNF1LK, SPOCD1, SPTAN1, SQSTM1,
ST3GAL6, STC2, STX3A, TFP12, TFP12, TGFBI, TGM2, THRAP1, TLN1, TMEM60,
TNFAIP3, TRIB3, TRIO, TSC2, UAP1L1, UBAP2L, UPP1, URB, USP11, USP5, VDR,
WDR4, YTHDF2, ZCCHC9, ZDHHC20, ZFHX1 B, ZNF185, ZNF278, ZNF690, ZNF697
Data obtained from our Microarray experiments disclose that Xanifolia Y
inhibiting gene
expression of the following genes (represented by gene symbol):
AKR1C3, SLC35A3, NEK9, CAV1, USP11, KRT7, TGM2, NCSTN, COG6, WDR4,
GPAA1, GUSB, UBAP2L, NMT2, C9orf10, KIAA0251, BTD, EMP1, KRT18, OS9,
CPSF1, PSMD1, RNPEP///UBE2V1 /// Kua /// Kua-UEV, NAGA, PARVA, HYOU1,
ARMC4, APEH, BTD, FER1 L3, CFH /// CFHL1, COL5A2, EFEMP1, COL18A1, HSDL2,
NUP188, IDS, PLOD1, CPM, SPTAN1, LAMP2, ARNTL2, PLOD2, KDELR3, KIAA0586,
SMARCA1, PRSS23, PTPRJ, LEPREL1, H2AFV, CAD, URB, CPNE3,
DKFZP586JO619, SERPINB7, CNAP1, EEF2K, IKBKAP, SLC25A21, KDELR3, PDIA6,
CAV2, COL4A2, MAGED2, PHF19, OACT2, JAG1, FAM62A, KDELR3, PIK4CA, USP5,
ZDHHC20, H2AFV, PTPRF, PEG10, P4HA1, MAGED2, PRSS23, PTPRF, CHRDL1,
C6orf65, APLP2, EXT2, COPG, SKIV2L, PDIA4, MYH9, SEC31 L1, GANAB, COL5A1,
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ZNF185, DDB1, HDLBP, AP2B1, TSC2, IPO4, FLNA, TLN1, PRKDC, COL6A3,
NTNG1, LEPR, RGS4, FN1, GPC6, LEPR, RGS4,IGFBP3
Data obtained from our Microarray experiments disclose that Xanifolia Y
stimulates
5 gene expression of the following genes (represented by gene symbol):
P8, KRTAP4-7, DUSP10, CLDN14, ANGPT2, DUSP10, GDF15, GPNMB, HDAC9,
HECW2, C14orf78, UPP1, PPP1R15A, PLEKHM1, STX3A, ANGPT2, SQSTM1,
RHOQ, STC2, PPP1 R1 5A, LOC286044, ATF3, HMOX1, CXCL2, CD33L3, LRRC8E,
SESN2, LIF, TFP12, KIAA1706, RRAGC, DDIT3, DYRK3, CTNS, GPNMB, CEBPB,
10 CCL20, AMIGO2, KIAA1462, HSPBAP1, EVC, CLN8, ABL2, SGEF, MCTP1, IRS2,
C14orf109, TNFAIP3, RND3, ZFHX1B, LHFPL2, SNF1LK, SLC3A2, NAV2, SPOCD1,
TFP12, EV12A, ST3GAL6, CSTB, ROBO4, GNPDA1, GEM, IRS2, HMGA2, PALM2-
AKAP2, BR13, KIAA1754, VDR, NEW, INSIGI, C17orf32, ABL2, PALM2-AKAP2,
MTERFD3, ZNF697, NFKBIZ, BCL6, THRAP1, MGC5618, ADAMTS1, MAFG, NPC2,
15 CITED2, TRIB3, ZCCHC9, RNU17D, CITED2, RRS1, NSUN5C, PBX2, RG9MTD1,
SGSH, INSIGI, MGC16291, RAB9A, ARMCX6, SERPINB2, ATP6V1B2,
DKFZP56411171, ATP6VOE, HSPC196, MRPS30, ARMCX1, LOC339229, ANKRD11,
C9orf103, PSEN2, ADAMTS1, SNAPC1, RNF25, ZNF278, TGFBI, UAP1L1, PDE4DIP,
MGC19764, TMEM60, CEP4, KIAA1211, DDX20, CSRP2BP, ZNF690, TRIO, CLTA,
20 ATP6VOE, RAB32, MRPS31, LOC90693, ATP6V1C1, CBLL1, YTHDF2, FLJ14466,
ARL10C, BCL2A1
Data obtained from our Microarray experiments disclose that Xanifolia YM(ACH-
Y)
stimulate gene expression of the following genes (represented by gene symbol):
25 YM stimulate the gene: Gene Symbol
CXCL2, CSF2, 1L6, NFKBIZ, CXCL3, EGR1, CLDN14, ATF3, IL1A, CSF3, PTGS2,
NFKBIZ, KRTAP4-9, TNFAIP3, ABL2, KRTAP4-7, MMP3, DUSP10, FOS, DUSP1,
PPP1R15A, DDIT3, DUSP10, HECW2, DSCR1, SESN2, TSLP, SLC7A11, HES1,
SESN2, CXCL1, TAGLN3, HBEGF, IER3, RAB2, P8, 1L8, GADD45A, LOC441461,
30 GEM, LIF, KLF6, MGC4504, CCL20, PRB1 /// PRB2, THRA /// NR1D1, ERN1,
NECAP2, DKK3, GNAO1, NFKBIA, CREB5, CLDN1, CDKN1A, PRDM1, SERPINB2,
CD274, FST, LOC401317, BIRC3, PMAIP1, BMP2, 1L24, BMP2, WHDC1L2, SGK,
RND3, UPP1, C14orf34, ARID1B, KLF6, KLHL24, MAFF, IL12A, SAT, NSD1, JUNB,
DUSP1, SLC3A2, ASNS, MAFF, PSAT1, CLTA, ZC3H12C, CLDN1, 11-1 13, ROBO4,
35 RARA, BCL6, SLC7A11, PDE4DIP, ZNF697, ATP2A2, ZFP36, REST, HDAC9, STAC2,
LOC153222, ZC3H12A, SLC25A37, IL17C, TRIB3, CEBPB, PTX3, TRIB3, KIAA1718,
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ZNF385, TTMP, MGC5618, CSF2, DUSP5, SLC25A25, ADAMTS1, TFRC, SEC15L2,
SCNNIA, HES1, LOC153222, C20orf72, ETS1, GDF15, KIAA1754, PACRG, PRSS22,
TFRC, AQP2, STX3A, REM1, LIMK2, STC2, ISG20L1, BCL2A1, HES4, TJP3, SLC7A5,
CEBPG, LILRB2 /// LILRB3, LOC389429, LLGL1, KLF6, CSNKIE, DUSP1, ICAM1,
PYY2, TPCN1, MFSD2, KIAA0690, SOD2, E2F7, GRIK5, PADI1, HIP1 R, IRAK2, EIF1,
CEBPG, GOS2, KIAA0690, NEDD4L, MXD1, TXNDC5, PERLD1, HIF1A, RDH13, CTH,
ETS2, FAH, CLK4, RIMS4, FLJ12355, LDLR, WARS, IFRD1, LRCH4, SLC1A4, FST,
PPIF, ARHGEF2, PMAIP1, PBEF1, C14orf159, ATF4, FLJ90119, TGFBR3, DDX21,
MUC8, TNFSF7, SPTLC2, KBTBD8, CIAS1, KIAA0476, NFKB1, DES /// FAM48A,
ICAM1, INHBA, MARS, Clorfll3, GRK6, TCF2, SLC7A1, TNFRSF10B, IER2, TFRC,
SOS2, CARS, HAB1 /// LOC442496, KLHL24, SQSTM1, GIT1, IRS2, SARS, TRIM25,
JUN, YRDC, ETS1, CTH, ABL2, CD274, FZD8, EREG, PFDN2, TMEM63B, DYRK3,
GARS, RASSF8, CAMTA2, HOXC8, AARS, TBX3, RRAGC, BCAP29, TNFRSF10B,
MCL1, PALM2-AKAP2, TMEM22, ZNF548, PCBP2, SLC1A4, FSTL3, TA-PP2C, PIM3,
MAFG, NOL1, PEA15, ETS2, IQCG, BEX2, C12orf39, LDLR, VEGF, CCNL1,
LOC440069, SNAPC1, SLC27A5, MARS, ICAM1, AXUD1, KCNIP2, LOC146177 ///
FLJ40941, GOT1, Cllorf17 /// NUAK2, TTBK1, SNCA, NFRKB, GRB2, ADAMTS1,
PALM2-AKAP2, CCNL1, JUN, SPRY4, SLC38A1, E2F7, MGC27165, IDS, SLC7A1,
FLJ11021, KCNK5, GYPC, MYC, CACNG6, PHLDA1, INSIG1, FLJ13448, LOC202051,
GALNT10, TFEB, ABL2, MTHFD2, SERPINB8,TNPO2, MCF2L, SERTAD1, SPRY2,
PHLDA1, SLC7A11, CXCL5, COMT, GTPBP2, RAB4B, ATXN7, OTUD5, VEGF,
ADAMTS6, YARS, NAV3, SAMD4, C17orf32, SHMT2, CHIC2, ORAOV1, CREM,
ALS2CL, AMIGO2, MGC19764, SFPQ, MGC11257, PLEKHM1, MMP28, SLC4A5,
DNAJB9, ERRF11, FZD8, MGC4399, GUCA1 B, ATP13A3, KIAA0020, XBP1,
ATP6V1B2, IGLV3-25, CHD4, GRB10, FLJ40089, CLDN19, NPC1, RIPK2, PLEKHF2,
LOC283314, RSPO3, GSK3A, ANKRD11, WARS, GNPDA1, IGKC /// IGKV1-5, RCL1,
C9orf9l, TIMM10, SLC1A4, ODC1, SLC38A1, EIF4EBP1, ZNF267, YRDC, CHD4,
PER1, NFKBIE, INSIG1, FLJ11259, NCOA3, TNPO2, BAZ2A, SLC1 A5, KRTAP2-1,
PDE4DIP, EPB41 L3, CITED2, JTV1, TA-PP2C, METRNL, BCL10, Clorfl9, PTP4A1,
PDE4DIP, CPSF1, TIMM10, IGSF21, TM4SF1, CDK6, BANP, PHLDA1, PAPPA2,
MGC17337, TNFRSF19L, ADAMTS10, CBFB, HERPUD1, RTTN, FLJ13855, SYNPO,
NAV2, FLJ34208, DDX10, C6orf66, LOC56902, CHMP1 B, HIPK2, H3F3B, NAV3,
ELL2, NSUN5C, PLAUR, UCK2, PBEF1, TP53BP2, TEX10, B3GNT5, USP36, INHBA,
SPIRE1, CSTB, NSUN5C, TFP12,
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Our experiment disclosed that Xanifolia Y and ACH-Y inhibited genes expression
of the
following genes: FN1, ITGAV, LAMA4, LAMB2, LAMC1, LAMB1, LAMB1, LAMA4,
LAMAS, LAMC1, LAMA2, LAMB1, LAMA3, SCAMP1, TICAM2, SCAMP1, TICAM2,
SCAMP1, SCAMP1, CAMK2B, DL1, ICAM3,CEECAM1,ICAM5,SCAMP1, CAMK1G,
CAMSAP1, MCAM, CAMTAI, CKN1, ALCAM, DCAMKL2, CEACAM3, CAMK2D,
CAMK2B, SCAMPS, CAMK4, NCAM1, CAMK2G, MYH9, MYH10, MYO1D, MYO5A,
MYLK, MYO6, MYO5A, MYO1 C, MYLK, MYO6, MYLC2PL, MYO10, MYO6, TPM3,
MYO1 C, BECN 1, MYO1E, TPM3, M-RIP, MYO1 B, MYO10, MYO5A, M-RIP, MYO10,
MYL6, MYOHD1, BECN1, TPM4, MYLK, MYH10, MYOHD1, LOC221875, LOC402643,
MYO15B, LOC129285, MYH11, MYO1 B, MYO1 C, MYO9B, CDH13, CTNNAL1, CDH13,
CDH12, CTNNB1, CDH5, CTNND1, CDH2, CTNNA1, CDH2, PCDHB16, CTNNA1,
CELSR2, PCDHB6, PCDHB7, CTNND2, PCDHGC3, PCDHGB4, PCDHGA8,
PCDHGA12, PCDHGC5, PCDHGC4, PCDHGB7, PCDHGB6, PCDHGB5, PCDHGB3,
PCDHGB2, PCDHGB1, PCDHGA11, PCDHGA10 , PCDHGA9, PCDHGA7, PCDHGA6,
PCDHGA5, PCDHGA4 , PCDHGA3 , PCDHGA2, PCDHGA1, CTNND1, CDH23,
PCDHB12, PCDHB10, PCDH18, CDH2O, PCDH9, PCDHGA12 , PCDHGA11,
PCDHGA10, PCDHGA6, PCDHGA5, PCDHGA3, PCDH7, CDH18, CDH6, CCBE1,
COL10A1, COL12A1, COL13A1, COL18A1, COL1A1, COL21A1, COL4A1, COL4A2,
COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL9A1, MMP9,
P4HA1, P4HA2, P4HB, PCOLCE, PCOLCE2, PCOTH, PLOD1, PLOD2, PLOD3, CIB1,
ILK, ITGA2, ITGA3, ITGA4, ITGA6, ITGAV, ITGB1, ITGB1 BP1, ITGB2, ITGB5,
ITGBL1,
TNC, EMILIN1, ICAM1, HSPG2, HPSE, HS2ST1,SDC2,
Determination of gene expression by Real-time PCR method (Brilliant QPCR,
Agilent Technologies): The real-time polymerase chain reactions further
confirm the
results obtained from micro array analysis. The Real-time PCR results (shown
below)
confirmed that Compound Y3 and YM increase the expression of the genes:
ANGPT2,
DDIT3, LIF and NFKB1Z
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Table 19:
ANGPT2 DDIT3 LIF NFKB1Z
of
control
Control 100 100 100 100
Y3 300 213 163 142.9
YM 216 660 447 784.8
YM = Y3 without
D = DMSO control Y = Y3 sugar
Table 20: The experimental results confirmed that compound Y3 inhibit the gene
expression of adhesion proteins: ITGAV, TNC, COL1 A1, FN1 and LAMA4
ITGAV TNC COL1 Al FN1 LAMA4
% of control
Control 100 100 100 100 100
Y3 63.8 41.1 49.9 44.1 53.6
With the same method, we also confirmed that the compound YM inhibits the
expression of adhesion proteins COD A1, FN1 and LAMA4
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Table 21:
COL1A1 FN1 LAMA4
% of control
Control 100 100 100
YM 42 72.8 81
ANGPT2 =angeopoietin 2, LIF = Leukemia inhibitory factor
ITGAV = integrin alpha V, (cholinergic differentiation factor),
TNC = Tenascin C, NFKB1 Z = nuclear factor of kappa light
COL1 Al = collagen type 1 alpha 1, polypeptide gene enhancer in B-cells
FN1 = fibronectin 1, inhibitor, zeta
LAMA4 = laminin alpha 4,
DDIT3 = DNA-damage-inducible transcript
3,
Data obtained from our Microarray experiments disclose that Xanifolia Y
modulates
gene expression.This invention provides compositions and methods for
modulating the
gene expression in cancer cells, wherein the modulating comprises of positive
and
negative regulation, wherein genes being modulatated are adhesion proteins;
wherein
modulation includes expression, production and secretion of adhesion proteins,
wherein the adhesion proteins comprise fibronectin, integrins family, Myosin ,
vitronectin, collagen, laminin, cadherin, heparin, Glypican, tenascin, CD 54,
CAM. This
invention provides compositions and methods for modulating angiopoietins,
wherein
comprises positive regulating the angiopoietin 2, wherein comprises negative
regulating
angiopoietin 1. The composition and method of this invention comprises a
triterpene
wherein acylation group at carbon position 21 and/or 22 of the triterpene is
necessary
for the function and are selected from angeloyl, acetyl, alkanoyl, and
alkenoyl and acyl
group. The sugar moiety (ies) at position 5 of the triterpene is important for
enchancing
activity of these compounds.
Leptin is a promoter in breast cancer cells. The Xanifolia Y and YM inhibits
the
expression of leptin.
The thrombospondins are a family of multifunctional proteins. The family
includes
thrombospondins 1-5. Thrombospondin-1 TSP1 is a multifunctional, matricellular
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glycoprotein, containing interacting domains for a large variety of adhesion,
migration
and proliferation, angiogenesis and tumor cell metastasis.
The insulin-like growth factor binding protein (IGFBP) is a multifunctional
protein that
5 relate to metastasis, tumor growth and angiogenesis. Compounds in this
application
modulate gene expression of RAB3B, inhibiting metastasis, tumor growth and
angiogenesis.
The activation of cell migration and cancer cells metastasis requires the
sensitive of
10 potassium channel. The results of the micro array experiment showed that
compound Y
and YM inhibit gene expression of family protein relate to potassium channel
in ES2
cells.
RAB3B is member RAS oncogene family protein. Compounds in this application
15 modulate gene expression of RAB3B, inhibiting metastasis, tumor growth and
angiogenesis.
In mild conditions, the saponin can be partially hydrolyzed into a mixture of
products
which are separated by HPLC. Specific partial hydrolysis of saponins can also
be
20 achieved with enzymes. The glycosidases catalyze the hydrolysis of the
glycosidic
linkage. Galactosidase is an enzyme which catalyzes the hydrolysis of
galactosides.
The glucosidase is an enzyme which breaks glucose from saponin. Other enzyme
examples are xylanases, lactase, amylase, chitinase, sucrase, maltase, and
neuraminidase.
The sugar moiety of the triterpenoid saponin (example Xanifolia Y) can be
removed by
acid hydrolysis. The synthetic compound of ACH-Y is obtained. The ACH-Y is a
triterpene with acyl groups but no sugar moiety. The acyl group of the saponin
(example
Xanifolia Y) can be removed by alkaline hydrolysis. A synthetic compound of
AKOH-Y
can be obtained. The AKOH-Y is a pentacyclic triterpene with sugar moieties. A
pentacyclic triterpene can be obtained by acid and alkaline hydroysis of
saponin from
natural source. A pentacyclic triterpene also can be obtained by other methods
(Reference: Surendra et al., Rapid and Enantioselective Synthetic Approches to
Germanicol and Other Pentacyclic Triterpenes). The pentacyclic triterpene with
sugar
moieties can also be obtained with synthesis (Reference: Ple et al., Synthesis
of L-
arabinopyranose containing hederagenin saponins). Acylation is the process of
adding
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61
an acyl group to a compound. Friedel-Crafts reaction is an example of the
process. An
active compound can be obtained by acylating a pentacyclic triterpene. In an
embodiment, acylating C21 and C22 of a pentacyclic triterpene gives an
anticancer
compound . In an embodiment, sugar moiety(s) at C3 can increase the activities
of
pentacyclic triterpene, wherein the triterpene has acyl group(s), wherein the
acyl
group(s) may be at C21, 22, or 28. In an embodiment, a sugar moiety is at C21,
22, or
28, wherein the sugar moiety is substituted with 2 acyl groups. Reference in
PCT/US/US05/319000, W020061029221, filed September 7, 2005, US1 1 /2891 42
filed
November 28, 2005)
Determination of cell growth of Leishmania parasites by MTT assay shows that
Y10 is
cytotoxic to Leishmania Major (promastigotes) with IC50 of 15ug/ml. IC 50 of Y
is
15ug/ml, YO is 25ug/ml, Y1 is 23ug/ml, Y5 is 16ug/ml, Y7 is 18ug/ml, ACH-Y Is
30ug/ml,
Mb5 is 15ug/ml, ACH-Mb5 is 18ug/ml, Z12 is 23ug/ml, and Bat is 15ug/ml
EXPERIMENTAL DETAILS
Experiment details of herb extraction, analysis of extract components by HPLC,
determination of the cell-growth activity effected by Xanifolia Y with cells
derived from
different human organs using MTT Assay, purification of the bioactive
components from
plant extract, fractionation of plant extracts with FPLC, isolation of
component Ys with
preparative HPLC, determination of the chemical structure, cell experiments
and animal
studying are disclosed in PCT/US05/31900, U.S. Serial No. 11/289142, U.S.
Serial
10/906303, U.S. Serial No. 11 /131551 and U.S. Serial Nos. 11 /683198, filed
on March 7,
2007, PCT/US2007/077273, filed August 30, 2007, U.S. Serial No. 60/890380,
filed on
February 16, 2007, U.S. Nos. 60/947,705, filed on July 3, 2007,
PCT/US2008/002086,
1188-ALA-PCT, filed February 15, 2008, the contents of which are incorporated
herein
by reference. Experiments 1-23 of PCT/US2008/002086, 1188-ALA-PCT, filed
February
15, 2008 are incorporated herein by reference.
Experiment 1: Removal of the sugar moiety from saponin by acid hydrolysis
15 mg saponin was dissolved in 1 ml of Methanol. 1 ml of 2N HCI was then
added.
The mixture was refluxed in 80C water bath for 5 hours. The solution was then
neutralized by adding 2 ml of 1 N NaOH (to final pH 4-6). The aglycone was
then
extracted with ethylacetate 3 ml x 2. The extracts were collected and pooled.
Further
isolation of aglycone (sugar-removed saponin) was achieved by HPLC with
isocratic
elution of 80-100% acetonitrile.
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Experiment 2: Removal of the acyl group by alkaline hydrolysis
Methods: 20 mg of saponin was dissolved in 0.5 ml of 1 M NaOH. The solution
was
incubated in 80C water bath for 4 hours. It was cooled to room temperature
before
neutralized with 0.5 ml 1 N HCI (adjust pH to about 3). The mixture was
extracted with 2
ml 1-butanol 3 times. The butanol fractions were collected and lyophilized.
The
hydrolyzed saponin with further purified with HPLC in a C-18 column eluted
with 25%
acetonitrile.
Experiment 3: Analysis of genesis of blood vessel in xenograft tumor treated
with
compound Y
Methods: Athymic Nu/Nu mice (5-6 weeks old) are divided into two groups (1 and
2)
with 5 animals in each group. On day 0, all mice were transplanted intra-
peritoneally
with one million ES2 (human ovarian cancer) cells. Animals were randomly
divided into
two groups:
Group 1: Control group. Animals did not receive drug-treatment.
Group 2: Drug-treatment group. On days 10-15 and 18-22, animals received daily
drug
administration of Xanifolia-Y, by i.p. route at dosage of 2.5 mg/kg.
Results: Animals showed high tumor burden after 18 days. Animals with high
tumor
burden were euthanized and solid tumors were taken out from these mice
(between 18-
27 days). Tumor tissues fixed with formalin at room temperature. The fixed
tissues
were sectioned and stained with Haematoxylin and eosin (H&E). The red blood
cells
inside the micro blood vessels were identified under a microscope. Figure 1
shows that
more blood vessels were observed in the control Groupl than those in the drug-
treated
Group 2
Experiment 4: Determination of cell growth of Leishmania parasites by MTT
assay.
Leishmania parasites (Leishmania major: MRHO/SU/59/P/LV39) were grown in
culture
medium in a T75 flask at room temperature. Promastigotes of Leishmania major
(approximately 40 million per ml) were used in the experiment. 1.2 ml cell
culture was
transferred to a well of the 24-wells plate. Saponin Y10 (0.2 ml in medium)
with different
concentrations (final 6.25 -200 ug/ml) was added to culture and cells were
grown for 1-5
days at room temperature. At the end of drug-treatment, 150 ul of MTT (5 mg/ml
in PBS)
was added to each well and incubated for 4 hours. Formazan formed in cells was
dissolved with DMSO and the OD at 490nm was determined by an ELISA reader.
CA 02715501 2010-08-12
WO 2009/117196 PCT/US2009/034115
63
Results: this experiment shows that Y10 is cytotoxic to Leishmania Major
(promastigotes) with IC50 approximately equal to 15ug/ml. Experiments are
repeated
with Y, ACH-Y, AKOH-Y, Mb5, ACH-Mb5, AKOH-Mb5 and Bal.
