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WO2008028060A2 - Composés antitumoraux servant à inhiber le développement du cancer - Google Patents

Composés antitumoraux servant à inhiber le développement du cancer Download PDF

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Publication number
WO2008028060A2
WO2008028060A2 PCT/US2007/077273 US2007077273W WO2008028060A2 WO 2008028060 A2 WO2008028060 A2 WO 2008028060A2 US 2007077273 W US2007077273 W US 2007077273W WO 2008028060 A2 WO2008028060 A2 WO 2008028060A2
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WO
WIPO (PCT)
Prior art keywords
cancer
angeloyl
ene
glucuronopyranosyl
compound
Prior art date
Application number
PCT/US2007/077273
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English (en)
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WO2008028060B1 (fr
WO2008028060A9 (fr
WO2008028060A3 (fr
Inventor
Pui-Kwong Chan
May Sung Mak
Original Assignee
Pacific Arrow Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pacific Arrow Limited filed Critical Pacific Arrow Limited
Priority to CN200780040744.4A priority Critical patent/CN101553497B/zh
Priority to EP07841638A priority patent/EP2061798A4/fr
Priority to PCT/US2008/002086 priority patent/WO2008133766A1/fr
Priority to EP08725693A priority patent/EP2121715A4/fr
Priority to JP2009550096A priority patent/JP2010519219A/ja
Priority to AU2008244648A priority patent/AU2008244648A1/en
Priority to SG2012011029A priority patent/SG178795A1/en
Priority to CN200880012065A priority patent/CN101772511A/zh
Priority to CA002676791A priority patent/CA2676791A1/fr
Publication of WO2008028060A2 publication Critical patent/WO2008028060A2/fr
Publication of WO2008028060A9 publication Critical patent/WO2008028060A9/fr
Publication of WO2008028060A3 publication Critical patent/WO2008028060A3/fr
Publication of WO2008028060B1 publication Critical patent/WO2008028060B1/fr
Priority to AU2009200988A priority patent/AU2009200988B2/en
Priority to US12/856,322 priority patent/US8586719B2/en
Priority to US13/841,053 priority patent/US9382285B2/en
Priority to US15/181,631 priority patent/US10213451B2/en
Priority to US16/285,634 priority patent/US11046724B2/en
Priority to US17/362,028 priority patent/US20220024961A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • Varicose veins are swollen and knotted veins that can occur in any part of the body, especially in the calf, inside leg or around the anus.
  • Escin has been satisfactorily used for treating Varicose veins and chronic venous insufficiency for many years.
  • Escin is a mixture of saponins found in the seed of the horse chestnut tree, Aesculus hippocastanum L, Hippocastanaceae.
  • Escin is the major active ingredient prepared from Aesculus hippocastanum (Hippocastanaceae), the horse chestnut tree.
  • aescin was shown to be as effective as compression therapy as an alternative to medical treatment for CVI. The therapeutic benefit is well supported by a number of experimental investigations in different animal models.
  • saponin compounds include: triterpenoid saponins and acylated prosapogenins from Harpullia austro-caledonica (Voutquenne et al. 2002); six triterpennoid saponins from Maesa laxiflora (Zhong et al. 1999); new triterpene saponin from Pittosporum vi ⁇ diflorum from the Madagascar rainforest (Young et al. 2002); anti-HIV-1 protease triterpenoid saponins from the seeds of Aesculus chinensis (Yang et al. 1999); triterpenoid saponins from the roots of Camellia sinensis var. assamica (Lu et al.
  • This invention shows that the saponins with two angeloyl groups have a strong activity for inhibiting cancers cells, anti-angiogenisis, inhibiting chronic venous insufficiency (CVI), shrinking hemorrhoids, inhibiting post-operative edema, rheumatism and cancerous cell growth.
  • CVI chronic venous insufficiency
  • shrinking hemorrhoids inhibiting post-operative edema, rheumatism and cancerous cell growth.
  • This invention discloses saponin compounds having the specific structures that are capable of inhibiting cancer or tumor cell growth.
  • Aquaporins is a family of transmembrane water-channel transporting proteins that play a major role in trans-cellular and transepithelial water movement. This invention shows that the triterpene saponins with two angeloyls have stronger activity for inhibiting cancer cell growth by affecting membrane functions. In an embodiment they affect the aquaporin and permeability of cell membrane.
  • This invention provides the uses of compounds comprising a triterpene or other sapongenin with two angeloyl groups, or at least two side groups selected from the following groups: angeloyl, tigloyl and/or senecioyl groups, wherein the side groups are attached to carbon
  • Xanifolia-Y is capable of extending the life span of animals bearing human tumors. These results show that it can be useful in treating cancers in mammal. In an embodiment it can be use in treating human cancers, preferably ovarian cancer.
  • Xanifolia-Y prolongs the life span of mice bearing of human tumor. It blocks the migration or metastasis of cancer cells. In an embodiment it affects adhesion proteins or interferes with the function of molecules on carcinoma cells or on the mesothelial cells. It inhibits the tumor growth in mammal. It is useful in cancer therapy. See Experiment 7, 8, 9, and 10.
  • This invention discloses saponin compounds having the specific structures are capable of inhibiting cancer or tumor cell growth and anti-angiogenesis.
  • This invention provides a method 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.
  • This invention relates to the mechanism of inhibiting cancer by regulating aquaporin in cancer cell and the interacting of aquaporin with compounds comprise a triterpene and two angeloyl groups.
  • the compound may be a saponin wherein comprises at least one angeloyl, preferable two angeloyl groups.
  • This invention relates to the aquaporin pathway that is influenced by saponins with angeloyl groups in inhibiting cancer.
  • FIG. 1 Structure of saponin comprising two angeloyl groups.
  • Figure 2 A, 2 B Structures of saponins
  • Figure 3 Structures of saponins
  • Figure 4 A and B Comparison of potency of compound Y (saponin with 2 angeloyl groups) and compound X (saponin with 1 angeloyl) in inhibiting growth of ovarian cancer cells.
  • the IC50 for Compound Y is about 1.5 ⁇ g/ml while 30 ⁇ g/ml for compound X.
  • Figure 4 C Inhibition of growth of skin cancer cells by the purified compound Y.
  • the IC50 is 0.23 ⁇ g/ml.
  • Figure 4 D Hemolytic activity of Xanifolia-Y, B-Escin, Xanifolia-X, ACH-Y and AKOH-Y Figure 5.
  • C. Compound Y inhibits tumor growth (IC50 4 ⁇ g/ml).
  • Figure 5 D Compare inhibition activity of Xanifolia-Y, B-Escin, Xanifolia-X and AKOH-Y Figure 6. Comparision of MTT and hemolytic activities of saponin compound and compound Ys. (A) and (B). Hemolytic activities; (C) and (D). MTT activities.
  • Figure 7. Saponin compound Y, X, ACH-Y, AKOH-Y and B-Escin These compounds are purified and their structures were verified by NMR and MS. These compounds are then used for MTT test.
  • Figure 10 A: HNBC of Y0.
  • Figure 12-16 show Xanifolia Y1 inhibits Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma Ovarian cancer, Renal cancer, Prostate cancer and Breast cancer activities
  • Figure 17-21 show Xanifolia Y2 inhibits Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma Ovarian cancer, Renal cancer, Prostate cancer and Breast cancer activities
  • Figure 22 Animal study result shows Group A Mice - Implanted tumor and no drug, Died on day 19-22; Group B Mice - Implanted tumor and with drug, survived over 50 days; Group
  • Figure 24 Animal study shows that the tumor size is 45% smaller in mice with drug than the mice with no drug in 10 days period.
  • Figure 25 Study apoptosis induced by Xanifolia-Y that apoptosis is a major form of cell death induced by Xanifolia-Y.
  • Figure 26EM study the effect of Xanifolia on membrane show that patches of pits were found in the membrane of Xanifolia-Y treated cells (Fig. 34B) but not in cells treated with the
  • DMSO Fig. 34A
  • AKOH-Y Fig. 34C
  • These pits have the size from 8OA to 500A (in diameter).
  • the pits represent holes formed in the membrane.
  • the pits are arranged in a characteristic pattern with smaller pits (8OA in diameter) located in the periphery and the bigger ones (500A in diameter) in the center.
  • the bigger holes are resulted from fusing of the smaller holes (Fig. 34D).
  • Figure 33 Compare the potency of Xanifolia Y in ovary and cervix cell.
  • Figure 34-36 show Xanifolia YO inhibits Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma Ovarian cancer, Renal cancer, Prostate cancer and Breast cancer activities
  • Figure 37-39 show Xanifolia Y9 inhibits Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma Ovarian cancer, Renal cancer, Prostate cancer and Breast cancer activities DETAILED DESCRIPTION OF THE INVENTION
  • This invention provides the results of a program for screening the bioactive compounds from natural plants.
  • 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, the contents of which are incorporated herein by reference
  • compositions comprising a triterpenoidal saponin.
  • the saponin has triterpenoid, triterpenoidal or other sapongenin, one or more sugar moieties and two angeloyl groups, or at least two side groups selected from the following groups: angeloyl groups, tigloyl groups or senecioyl groups, wherein the side groups are attached to the sapongenin backbone at carbon 21 and 22.
  • compositions comprising the structures comprising at least two side groups selected from the following groups: angeloyl, tigloyl or senecioyl groups, wherein the side groups are attached to a triterpenoidal, triterpenoid, triterpenoidal or other sapongenin backbone.
  • side groups selected from the following groups: angeloyl, tigloyl or senecioyl groups, wherein the side groups are attached to a triterpenoidal, triterpenoid, triterpenoidal or other sapongenin backbone.
  • This invention provides a method of preparing the saponins, comprising the steps of:
  • Fractionation may be achieved by HPLC and FPLC chromatography with silica gel, C18 or other equivalent solid phase materials; (g) Monitoring the fractionating, if using HPLC or FPLC, the absorption wavelength at 207nm to 500nm may be used; (h) Identifying the bioactive components of the crude extract; (i) Purifying one or more bioactive components of the crude extract with FPLC to obtain one or more fractions of the bioactive component; and (j) isolating the bioactive components with chromatographic techniques that employ preparative columns and HPLC.
  • this invention provides the method of MTT Assay to test the bioactivities of the saponins or other compounds.
  • HTB-9 (bladder), HeLa-S3 (cervix), DU 145 (prostate), H460 (lung), MCF-7 (breast), K562 (leukocytes), HCT116 (colon), HepG2 (liver), U2OS (bone), T98G (brain), SK-MEL-5 (Skin) and OVCAR-3 (ovary).
  • the cells were grown in following culture media: HeLa-S3, DU 145, MCF-7, Hep-G2 and T98G are in MEN (Earle's salts); HTB-9, H460, K562 and OVCAR-3 in RPMI-1640; HCT-1 16 and U2OS in McCoy-5A. They are supplemented with 10% fetal calf serum, glutamine and antibiotics, and incubated in an incubator with 5% CO 2 humidified at 37 0 C.
  • MTT Assay The procedure for MTT assay followed the method described by Carmichael et al.(1987) with modifications.
  • the cells were seeded into a 96-well plate at concentration of 10,000/well for HTB-9, HeLa, H460, HCT116, T98G and OVCAR-3), 15,000/well for DU145, MCF-7, HepG2 and U2OS), and 40,000/well for K562 for 24 hours before drug- treatment.
  • the cells were then exposed to the drugs for 48 hours (72 hours for HepG2 and U2OS, and 96 hours for MCF-7). After the drug-treatment, MTT (0.5 mg/mL) was added to cultures and incubated for an hour.
  • the formazan product of the reduction of tetrazolium by viable cells formed and was dissolved with DMSO and the O. D. at 490nm, and was measured by an ELISA reader.
  • the MTT level of the cells before drug-treatment was also measured (TO).
  • %LC (TD-TO / TO) x 100(2).
  • This invention provides a composition that effectively reduced or inhibitied the cancer cell growth, wherein the cancer includes but is not limited to bladder cancer, bone cancer and ovary cancer.
  • This invention provides a composition comprising an effective amount of triterpenoidal saponins named as Xanifolia Y1 , Y2, Y, Y7, Y8, Y9, Y10, YO or their derivatives for treating 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 pain; for reducing symptoms of stomach pain; for reducing symptoms of leg pain; for treating pruritis, lower leg volume, thrombosis, thromophlebitis; for treating rheumatism; for preventing gastric ulcers antispasmotic and inhibiting tumor growth.
  • This invention provides a method of inhibiting cancer cell growth by affecting the aquaporin protein.
  • This invention provides a method of inhibiting tumor growth in a subject comprising administering contracting an effective amount of compounds in this invention to the subject affecting or interacting the aquaporin protien at the surface of cancer cell.
  • the compound comprises two angeloyl groups.
  • the compound may be selected from formula (1 ), (1A), (1B), (1C) and (1 D).
  • the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
  • the compound(s) are selected from Xanifolia (YO, Y1 , Y2, Y, Y7, Y8, Y9, and Y10).
  • the compound(s) are selected from Xanifolia (x), Escin or Aescin.
  • the compound(s) are selected from Compound A to X and A1 to X1 in the application.
  • This invention provides a method of inhibiting cancer cell growth by increasing the static charge of the cell, wherein increase water flow in the cell.
  • the charged molecules or ions pass cell membrane through channel protein and kill cancer cell.
  • the term “inhibit” encompasses prevent, and killing of the said cancer or tumor cell
  • This invention provides a method interacting with aquaporin protein for regulating the water channel, modulating the secretion, regulating the water metabolism of body, reducing the amount of urine, reducing urinate times, treating enuresis, treating frequent urination.
  • the method comprises administering contracting an effective amount of compounds to the subject affecting or interacting with the aquaporin protein at the surface of caner cell.
  • the compound comprises two angeloyl groups.
  • the compound may be selected from formula (1 ), (1A), (1 B) and (1 D).
  • the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
  • the compound comprises a triterpene backbone, two acetyl groups with 2 or more carbon and sugar moiety.
  • the compound(s) are selected from Xanifolia (YO, Y1 , Y2, Y, Y7, Y8, Y9, and Y10). In an embodiment the compound(s) are selected from Xanifolia (x), Escin or Aescin. In an embodiment the compound(s) are selected from Compound A to X and A1 to X1 in the application.
  • This invention provides uses compound comprises a triterpene and angeloyl groups interacting with aquaporin protein for regulating the water channel, modulating the secretion, treating enuresis, inhibiting tumor growth, stopping cancer cell proliferate. In an embodiment, compound interacting with aquaporin protein for regulating the water channel, modulating the secretion, destroying the cancer cell.
  • This invention provides a composition interacting with aquaporin protein for regulating the water channel, modulating the secretion, treating enuresis, inhibiting tumor growth.
  • a composition comprising an effective amount of the compound of any one of YO, Y1 , Y2, Y,Y7, Y8, Y9, Y10, or a salt, ester, metabolite or derivative thereof as a medicament 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.
  • the aquaporins are a family of homologous water channels expressed in many epithelial and endothelial cell types involved in fluid transport.
  • the family of mammalian AQPs consists of 11 members, AQP0-10, each with a distinct tissue. Functional measurements indicate that mammalian AQPs 1 , 2, 4, 5, and 8 are probably water selective, whereas AQPs 3, 7, 9, and 10 also transport glycerol and other small solutes. They are expressed at part of membrane of cell.
  • AQP1 protein is strongly expressed in most microvessel endothelia outside of the brain, as well as in endothelial cells in cornea, intestinal lacteals, and in other tissues
  • AQP 1 protein was strongly expressed in the membrane of microvessels and small vessels in all ovarian epithelial tumors, but less at the cytoplasm of tumor cells. In addition, AQP1 protein was also observed in the membrane of interstitial cells of ovarian carcinoma. Incorporated by reference of: The influence of aquaporin-1 and microvessel density on ovarian carcinogenesis and ascites formation, J. H. Yang et al., 2006 IGCS, International Journal of Gynecological Cancer 16 (suppl. 1 )
  • the distribution amount of AQPs 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 are varied at membrane of different cells.
  • certain type of Aquaporin proteins is over-expressed.
  • An increasing number of disturbances have been found associated to abnormal function of these proteins.
  • the compounds Xanifolia can interact with the aquaporin and inhibit the tumor cell growth.
  • a Western blot is a common method in molecular biology/biochemistry/immunogenetics to detect protein in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate proteins by mass. The proteins are then transferred out of the gel and onto a membrane, where they are "probed” using antibodies specific to the aquaporin protein. As a result, we can examine the amount of aquaporin protein in a given sample and compare levels between several groups. Other techniques which allow detection of proteins in tissues (immunohistochemistry) and cells (immunoctochemistry) are used. Other methods such as Bradford protien assay, UV spectroscopy, Biuret protein assay, Lowry protien assay, Bicinchonic acid protein assay may also be used.
  • This invention describes a method of destroying cancer cell or inhibiting the cancer cell proliferates by regulating or affecting the aquaporin.
  • the saponin with two angeloyl groups can interacts with the aquaporin in order inhibiting the cancer cell growth.
  • the compound may be selected from formula (1 ), (1A), (1 B) (1C) and (1 D).
  • the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
  • the compound comprises a triterpene backbone, two acetyl groups with 2 or more carbon and sugar moiety.
  • the compound(s) are selected from Xanifolia (YO, Y1 , Y2, Y, Y7, Y8, Y9, and Y10). In an embodiment the compound(s) are selected from Xanifolia (x), Escin or Aescin. In an embodiment the compound(s) are selected from Compound A to X and A1 to X1 in the application.
  • the method is blocking the cancer cell proliferates by regulating, interacting or affecting the aquaporin. In embodiment, the method is increase the water permeability of the cell membrane by regulating or affecting the aquaporin in order to kill the cell. In an embodiment, the method is affecting the aquaporin permitting extra water into the cell to damage the cancer cell. In an embodiment, the method is affecting the aquaporin permitting Glycerol related solute into the cell to damage the cancer cell. In an embodiment, the method is affecting the aquaporin regulating water into the cell to damage the cancer cell, wherein the method comprise compound selecting from Xanifolia (YO, Y1 , Y2, Y, Y7, Y8, Y9, and Y10).
  • the method is adjusting the fluid density outside the cell in order to damage the cancer cell by regulating the fluid pass in the cell wherein the aquaporin is overexpressed.
  • this invention makes use of the change of cell membrane permeability to damage the cancer cells.
  • the cell membrane permeability can be changed by the overexpression of some aquaporins.
  • the potency of Xanifolia(Y) is difference in different cancer cells of ovary, cervix, lung, skin and breast because they have variation of Aquaporin (AQPs 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10) at the membrane.
  • Amount of Aquarpoin (AQP 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10) at the membrane in various types of ovarian cancer cells such as OVCAR3, SKOV3, TOV21 G and ES2 is different , therefore they show different inhibition activity when treated with Xanifolia (Y).
  • Xanifolia (Y) is a saponin comprises a triterpene, two angeloyl groups and sugar moiety.
  • the compounds of this invention interact with cancer cells and increase the static charge of the cells.
  • the static charge increase water flow into the cells.
  • the cancer cells are collaped.
  • This invention describes a method interacting or regulating the protein on the surface of a cell or altering the functional properties of intracellular membranes or regulating the fluid passage through the cell wall or softening the skin or improving the skin structure, comprising administering to a subject.
  • This invention describes a method of regulating or affecting the aquaporin, wherein the method comprising the uses of compositions comprising a triterpenoidal saponin.
  • the saponin has triterpenoid, triterpenoidal or other sapongenin, one or more sugar moieties and two angeloyl groups, or at least two side groups selected from the following groups: angeloyl groups, tigloyl groups or senecioyl groups, wherein the side groups are attached to the sapongenin backbone at carbon 21 and 22.
  • the sugar moiety comprises at least one or more of 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.
  • the method comprise the use of a composition comprising the structures comprising at least two side groups selected from the following groups: angeloyl, tigloyl or senecioyl groups, wherein the side groups are attached to a triterpenoidal, triterpenoid, triterpenoidal or other sapongenin backbone.
  • a composition comprising the structures comprising at least two side groups selected from the following groups: angeloyl, tigloyl or senecioyl groups, wherein the side groups are attached to a triterpenoidal, triterpenoid, triterpenoidal or other sapongenin backbone.
  • composition comprising an effective amount of six novel saponin compounds with the diangeloyl groups (Y1 , Y2, Y, Y8, Y9, Y10) and their structures are as follows. They have anti-cancer and hemotylic effect activies. These six compounds were determined in U.S. Serial 10/906303, International Application No. PCT/US2005/031900. and U.S. Serial 11/131551 , the contents of which are incorporated herein by reference.
  • This invention provides a bioactive compound Xanifolia X, oleanene triterpenoidal saponin with a trisaccharide chain attached at C-3 and one angeloyl group acylated at C-22.
  • the saponin is isolated from extract of Xanthoceras sorbifolia.
  • the formula of X is C58H9 2 O 22 and the chemical name is: 3-O- ⁇ [/?-D-galactopyranosyl (1 ⁇ 2)]-[ «-L-arabinofuranosyl (1 ⁇ 3)]-/?- D-glucuronopyranoside butyl ester ⁇ -21-O-acetyl-22-O-angeloyl-3y?,16 ⁇ ,21#22 ⁇ ,28- pentahydroxyolean-12-ene.
  • the chemical structure of compound X is presented in the following figure.
  • This invention provides a bioactive compound Xanifolia YO and the chemical name is: 3-O-[ ⁇ -D-galactopyranosyl(1 ⁇ 2)]- ⁇ -L-arabinofuranosyl(1 ⁇ 3)- ⁇ -D-glucuronopyranosyl-21- O-angeloyl, 22-O-(2-methylpropanoyl)-3 ⁇ , 15 ⁇ , 16 ⁇ , 21 ⁇ , 22 ⁇ , 28-hexahydroxyolean-12- ene,
  • This invention provides a bioactive compound Xanifolia Y7 and the chemical name is:
  • This invention provides a method of treating a mammal for treating cancers comprising administering to said mammal a therapeutically 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, 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 comprise Xanifolia YO, Y1 , Y2, w , Y7,Y8, Y9, Y10, or a salt, ester, metabolite or derivative thereof.
  • the compounds of this invention can be isolated from natural sources or synthesized.
  • a salt of compound comprise sodium salt, potassium salt or calcium salt.
  • a salt of compounds comprise the following:
  • composition comprising an effective amount of a compound selected from formula (1 ):
  • R1 and R2 comprises angeloyl group; R3 comprises H or OH; R4 comprises CH 2 OR6, and wherein R6 is H; R5 comprises at least one sugar moiety comprising sugar or its derivatives; R8 may be OH.
  • R1 and R2 comprise an angeloyl group; R3 comprises H or OH; R4 comprises COOR6 wherein R6 is H.
  • R1 comprises H; R2 comprises an angeloyl group; R3 comprises H or OH; R4 comprises CH 2 OR6 or COOR6; wherein R6 is an angeloyl group.
  • R4 comprises CH 2 OR6 or COOR6; at least two of R1 , R2, and R6 comprise an angeloyl group or an acid having five carbons; R3 represents H or OH; and wherein R6 is an angeloyl group, H, acetyl group, tigloyl group, senecioly group, or an acid having two to five carbons.
  • at least one angeloyl of R1 or R2 is replaced by an acetyl group, tigloyl group, senecioly group, or an acid having two to five carbons;
  • R3 comprises H or OH;
  • R4 comprises CH 2 OR6 or COOR6; and wherein R6 is angeloyl group.
  • the R4 comprises CH 2 OR6 or COOR6; and wherein R6 is H or acetyl.
  • at least one of R1 , R2 and R4 comprises a sugar moiety or a side chain comprising sugar or its derivatives, wherein the sugar moiety comprises at least two angeloyl groups, acetyl group, tigloyl group, senecioly group, or an acid having two to five carbons or combination thereof.
  • position C23, C24, C25, C26, C29 and C30 independently comprises CH 3 , CH 2 OH, CHO, COOH, alkyls group, acetyl group or their derivatives thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises one or more sugar of, but not 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.
  • the sugar moiety comprises one or more sugar of, but not limited to, glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, or alduronic acid: glucur
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises two sugars selected from D-glucose, D-galactose, L-rhamnose, L-arabinose, D-xylose, or their alduronic acids: D-glucuronic acid, D-galacturonic acid, and their derivatives thereof, and the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises three sugars selected from D-glucose, D-galactose, L-rhamnose, L-arabinose, D- xylose, derivatives: alduronic acid, D-glucuronic acid, D-galacturonic acid, and their derivatives thereof, and the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises three sugars selected from D-glucose, D- galactose, L-rhamnose, L-arabinose, D-xylose, and their derivatives thereof, and the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises at least one sugar selected from D-glucose, D-galactose, L-rhamnose, L- arabinose, D-xylose, or alduronic acid: D-glucuronic acid, D-galacturonic acid or derivatives thereof, or the combination thereof.
  • R5 comprises a sugar moiety comprising glucose, galactose, arabinose or their aldironic acids thereof, or their combination thereof.
  • R5 comprises a side chain capable of performing the function of the sugar moiety.
  • the R5 represents H.
  • R4 represents H, OH or CH 3 .
  • R1 or/and R2 is a functional group capable of performing the function of the angeloyl.
  • R5 comprises a side chain capable of performing the function of the sugar moiety.
  • a sugar moiety is a side chain (segment of molecule) comprising one or more sugars or their aldironic acids thereof, or derivative thereof. Substitution, deletion and/or addition of any group or groups in the above-described compounds by other group or groups will be apparent to one of ordinary skill in the art based on the teaching of this application.
  • 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.
  • composition comprising effective amounts of compounds selected from formula (1A):
  • (1A) also named as (1A), or a salt, acid, ester, metabolite or derivative thereof, wherein R1 and R2 independently comprise an angeloyl group; R3 comprises H or OH; R4 comprises CH 2 OR6; and wherein
  • R6 is H; R8 may be OH; R5 comprises at least one sugar moiety or its derivatives.
  • R1 and R2 independently cor-nrise an angeloyl group; R3 comprises H or OH; R4 comprises COOR6 wherein R6 is H; R5 comprises at least one sugar moiety or its derivatives.
  • R1 comprises H; R2 comprises angeloyl group; R3 comprises H or OH; R4 comprises CH 2 OR6 or COOR6; wherein R6 is an angeloyl group; and R5 comprises at least one sugar moiety or its derivatives.
  • R3 comprises H or OH
  • R4 comprises CH 2 OR6 or COOR6
  • R6 is an angeloyl group, H, acetyl group, tigloyl group, senecioyl group, or an acid having two to five carbons
  • at least two of R1 , R2, and R6 comprise an angeloyl group or an acid having five carbons
  • R5 represents at least one sugar moiety or its derivatives.
  • At least one angeloyl from R1 or R2 is replaced by an acetyl group, tigloyl group, senecioyl group, or an acid having two to five carbons;
  • R3 represents H or OH;
  • R4 comprises CH 2 OR6 or COOR6 wherein R6 is angeloyl group;
  • R5 comprises at least one sugar moiety or its derivatives.
  • R4 comprises CH 2 OR6 or COOR6; at least one of R1 , R2, and R6 is a sugar moiety comprising at least two angeloyl groups, acetyl group, tigloyl group, senecioyl group, or an acid having two to five carbons or combination thereof.
  • position 24 of the compound comprises CH 3 or CH 2 OH.
  • position C23, C24, C25, C26, C29, and C30 of the compound independently comprises CH 3 Or CH 2 OH.
  • position C23, C24, C25, C26, C29 and C30 of the compound independently comprises CH 3 , CH 2 OH, CHO, COOH, COO-alkyl, COO-aryl, COO- heterocyclic, COO-heteroaryl, CH 2 O-aryl, CH 2 O-heterocyclic, CH 2 O- heteroaryl, alkyls group, acetyl group or derivative thereof.
  • R5 comprises a sugar moiety and alduronic acid selected from glucose, galactose, arabinose, glucuronic acid, galacturonic acid, or derivative thereof, or the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises at least one sugar of, but is not limited, to D-glucose, D-galactose, L-rhamnose, L-arabinose or D-xylose, or alduronic acid: D-glucuronic acid, D-galacturonic acid, or derivatives thereof, or the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises two sugars comprising but not limited to, D-glucose, D-galactose, L-rhamnose, L- arabinose or D-xylose, or alduronic acid: D-glucuronic acid, D-galacturonic acid, or derivative thereof, or the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises at least three sugars selected from but not limited to, D-glucose, D-galactose, L-rhamnose, L-arabinose, D-xylose, or alduronic acid: D- glucuronic acid, D-galacturonic acid, or derivative thereof, or the combination thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises at least one sugar of, but is not limited to, glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose or fructose, or alternatively alduronic acid, glucuronic acid, galacturonic acid, or derivative thereof, or the combination thereof.
  • the sugar moiety comprises at least one sugar of, but is not limited to, glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose or fructose, or alternatively alduronic
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises three sugars selected from, but not limited to, glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose or fructose, or alduronic acid: glucuronic acid and galacturonic acid, or/and derivative thereof, or/and the combination thereof.
  • sugar moiety comprises three sugars selected from, but not limited to, glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose or fructose, or alduronic acid:
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises three sugars selected from, but not limited to, glucose, galactose, rhamnose, arabinose, xylose or fucose, or/and derivative thereof, or/and the combination thereof.
  • R5 comprises a compound capable of performing the function of the sugar moiety.
  • the R5 represents H.
  • R4 represents H or OH or CH 3 .
  • R1 or/and R2 is a functional group capable of performing the function of the angeloyl group.
  • R5 represents a side chain capable of performing the function of the sugar moiety.
  • R1 and R2 are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl.
  • R1 and R2 comprise angeloyl, tigloyl, senecioyl, benzoyl or alkenoyl.
  • R4 represents CH 2 OR6; at least two of R1 , R2 and R6 are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl.
  • R4 represents CH 2 OR6; at least two of R1 , R2 and R6 are selected from angeloyl, tigloyl, senecioyl, benzoyl or alkenoyl.
  • R4 represents CH 2 OR6; at least two of R1 , R2 and R6 are selected from angeloyl, benzoyl or alkenoyl.
  • R1 and R2 are selected from H, angeloyl, acetyl, tigloyl, senecioyl, alkyl, acyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, heterocylic or heteroraryl;
  • R4 represents CH 2 OR6 or COOR6; wherein R6 is selected from H, COCH 3 , angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or
  • R4 represents CH 2 OR6, COOR6 or CH 2 COOR6; at least two of R1 , R2 and R6 are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • At least two of R1 , R2 and R4 are comprising angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • at least two of R1 , R2 and R4 comprise angeloyl, acetyl, tigloyl, senecioyl, benzoyl or alkenoyl, or a derivative thereof.
  • At least two of R1 , R2 and R4 comprise angeloyl, tigloyl, senecioyl, benzoyl or alkenoyl, or a derivative thereof. In an embodiment, at least two of R1 , R2 and R4 comprise a side chian capable of performing the function of the angeloyl group. In an embodiment, at least two of R1 , R2 and R4 comprise a side chian capable of performing the function of benzoyl. In an embodiment, R4 represents CH 2 OR6,
  • R2 and R6 are selected from angeloyl, tigloyl, senecioyl, benzoyl, alkenoyl, benzoyl or derivatives thereof.
  • R4 represents CH 2 OR6, COOR6 or CH 2 COOR6;
  • R1 , R2 and/or R6 is/are a sugar moiety comprising groups selected from H, angeloyl, acetyl, tigloyl, senecioly, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R4 represents CH 2 OR6, COOR6 or CH 2 COOR6;
  • R1 , R2 and/or R6 is/are a sugar moiety comprising at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R4 represents CH 2 OR6, COOR6 or CH 2 COOR6; R1 , R2 and/or R6 is/are a sugar moiety comprising at least 2 groups selected from angeloyl, tigloyl, senecioyl, benzoyl, alkenoyl or a derivative thereof.
  • R4 represents CH 2 OR6, COOR6 or CH 2 COOR6; R1 , R2 and/or R6 is/are a sugar moiety comprising at least 2 groups selected from angeloyl, benzoyl, alkenoyl or a derivative thereof.
  • a compound selected from formula (1A) comprising at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, or derivative thereof or a group capable of performing the function of angeloyl.
  • a compound selected from a formula (1A) comprises at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • a compound selected from a formula (1A) comprises a sugar moiety or a side chain of performing function of sugar moiety comprising at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, or a derivative thereof or a group capable of performing the function of angeloyl.
  • a compound selected from a formula (1A) comprises a sugar moiety or a side chain capable of performing the function of a sugar moiety comprising at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R4 is a group comprising CH 2 OCOCH 3 , CH 2 COO-alkyl, CH 2 OH, COOH, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • a sugar moiety is a segment of a molecule comprising one or more sugars or their aldironic acids thereof, or a derivative thereof.
  • the compounds of this invention can be isolated from natural sources or synthesized.
  • substitution, deletion and/or addition of any group in the above-described by other groups will be apparent to one of ordinary skill in the art based on the teachings of this application.
  • 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 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 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.
  • This invention provides uses of a compound selected from a compound with formula (1 B):
  • R1 comprises a group selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, dibenzoyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivatives thereof;
  • R2 comprises a group selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, hetero
  • R5 comprises hydrogen, alkly, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, acyl, alkanoyl, cycloalkanoyl, alkenoyl, cycloalkenoyl, aryloyl or heteroaryloyl.
  • R1 comprises a sugar moiety wherein at least two groups are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl , acid with carbon 2-6, or a derivative thereof.
  • R1 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, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl , acid with carbon 2-6, or a derivative thereof.
  • 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 or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl , acid with carbon 2-6, or a derivative thereof.
  • R2 comprises a sugar moiety or a side chain wherein at least two groups are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl , acid with carbon 2-6, or a derivative thereof.
  • R4 comprises CH 2 OR6, COOR6 wherein R6 is a sugar moiety which comprises at least one group selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl , acid with carbon 2-6, or a derivative thereof.
  • R6 is a sugar moiety which comprises at least one group selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkano
  • R4 comprises CH 2 OR6, COOR6, wherein R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substitutedalkanoyl, aryl, acyl, heterocylic or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6, or a derivative thereof.
  • R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substitutedalkanoy
  • R4 represents CH 2 OR6, COOR6, wherein R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, or alkyl.
  • R4 comprises CH 2 OR6, COOR6 wherein R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, dibenzoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl , acid with carbon 2-6, or a derivative thereof.
  • R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, dibenzoyl,
  • R4 comprises CH 2 OR6, COOR6 of formula (1 B), at least two of R1 , R2 and R6 comprise the group selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6, or a derivative thereof.
  • R4 comprises CH 2 OR6, COOR6 of formula (1 B), at least two of R1 , R2 and R6 comprise angeloyl, benzoyl, alkenoyl, or a derivative thereof.
  • R4 is a side chain comprising CH 2 OCOCH 3 , CH 2 COO-alkyl, CH 2 OH, COOH, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl , cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6, or a derivative thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises one or more sugar of, but is not 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.
  • R5 comprises a sugar moiety or a group capable of performing the function of the sugar moiety.
  • the R5 represents H.
  • R4 represents H, OH or CH 3 .
  • position C23, C24, C25, C26, C29 and C30 of the compound independently comprise CH 3 , CH 2 OH, CHO, COOH, COOa-lkyl, COO-aryl, COO-heterocyclic, COO-heteroaryl, CH 2 Oaryl, CH 2 O- heterocyclic, CH 2 O- heteroaryl, alkyls group, acetyl group or derivatives thereof.
  • C23, C24, C25, C26, C29 and C30 of the compound independently comprise alkly, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, acyl, alkanoyl, cycloalkanoyl, alkenoyl, cycloalkenoyl, aryloyl or heteroaryloyl;
  • R1 and R2 independently comprise an angeloyl group.
  • R1 is a sugar moiety or a side chain which comprise two angeloyl groups.
  • R1 and R2 independently comprise a benzoyl group.
  • R1 is a sugar moiety which has two benzoly groups.
  • R 3 represents H or OH.
  • R8 may be OH.
  • R8 comprises alkly, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, acyl, alkanoyl, cycloalkanoyl, alkenoyl, cycloalkenoyl, aryloyl, heteroaryloyl.
  • the R3, R4, R8 or R5 comprise N.
  • the spatially adjacent OH groups derivatized to form a cyclic five or six- membered ring comprising dioxole or cyclic carbonate.
  • 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.
  • 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 composition comprising an effective amount of the compound selected from the above formula or a salt, ester, metabolite or derivative thereof as a medicament 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.
  • This invention provides uses of a compound selected from a compound with formula (1C): also named as (1C), or a salt, ester, metabolite or derivative thereof, wherein R1 and R2 independently comprise an angeloyl group; R3 represents H or OH; R4 comprises CH 2 OR6, wherein R6 is H; R5 comprises a sugar moiety comprising one or more sugars of D-glucose, D-galactose or its derivatives. R7 represents COOH.
  • R1 and R2 independently comprise an angeloyl group; R3 represents H or OH; R4 comprises COOR6 wherein R6 is H; R5 comprises a sugar moiety comprising one or more sugars of D-glucose, D-galactose or its derivatives. R7 represent COOH.
  • R1 represents H; R2 comprises angeloyl group; R3 represents H or OH; R4 comprises CH 2 OR6 or COOR6, wherein R6 comprises an angeloyl group or acetyl group.
  • At least two of R1 , R2, and R6 comprise an angeloyl group or acid having five carbons;
  • R3 represents H or OH;
  • R4 comprises CH 2 OR6 or COOR6, wherein R6 is angeloyl group, H, acetyl group, tigloyl group, senecioyl group, or an acid having two to five carbons.
  • at least one angeloyl from R1 or R2 is replaced by an acetyl group, tigloyl group, senecioyl group, or an acid having two to five carbons;
  • R3 represents H or OH;
  • R4 represents CH 2 OR6 or COOR6, wherein R6 is angeloyl group.
  • R4 comprises CH 2 OR6 or COOR6; at least one of R1 , R2, and R6 is a sugar moiety comprising at least two angeloyl groups, acetyl group, tigloyl group, senecioyl group, or an acid having two to five carbons or combination thereof.
  • position C24 of the compound comprises CH 3 or CH 2 OH.
  • R7 represents CH 3 , CH 2 OH, CHO, COOH, COO-alkyl, COO- aryl, COO-heterocyclic, COO-heteroaryl, CH 2 Oaryl, CH 2 O-heterocyclic, CH 2 O- heteroaryl, alkyls group, acetyl group or derivatives thereof.
  • position of C23, C24, C25, C26, C29 and C30 of the compound indepentent ly comprises CH 3 or CH 2 OH.
  • position of C23, C24, C25, C26, C29 and C30 of the compound respectively comprise CH 3 , CH 2 OH, CHO, COOH, COO-alkyl, COO-aryl, COO-heterocyclic, COO- heteroaryl, CH 2 Oaryl, CH 2 O-heterocyclic, CH 2 O-heteroaryl, alkyls group, acetyl group or derivative thereof.
  • R5 comprises a sugar moiety comprising one or more sugars of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, or alternatively alduronic acid or glucuronic acid or galacturonic acid, or derivative thereof, or the combination thereof.
  • the R5 represents H.
  • R4 comprises H, OH, or CH 3 CH 2 OR6, wherein R6 comprises H or an acetyl group.
  • R1 or/and R2 is a functional group capable of performing the function of the angeloyl.
  • R5 represents a side chain capab l ⁇ of performing the function of the sugar moiety.
  • R1 and R2 are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivatives thereof.
  • R1 or/and R2 is a sugar moiety comprising two of groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivatives thereof.
  • R1 and R2 are selected from H, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl;
  • R4 represents CH 2 OR6 or COOR6, wherein R6 is selected from H, COCH 3 , angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivatives thereof.
  • R4 comprises CH 2 OR6, COOR6 or CH 2 COOR6; at least two of R1 , R2 and R6 are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivatives thereof.
  • R4 comprises CH 2 OR6, COOR6 or CH 2 COOR6;
  • R1 , R2 and/or R6 is/are a sugar moiety, which comprises at least 2 groups selected from H, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivatives thereof.
  • a compound selected from formula (1C) comprises at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, or derivatives thereof or a group capable of performing the function of angeloyl.
  • a compound selected from formula (1C) comprises at least 2 groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivatives thereof.
  • R4 is a compound comprising CH 2 OCOCH 3 , CH 2 COO-alkyl, CH 2 OH, COOH, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • 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.
  • 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 of a compound selected from a compound of formula (1 D): and also named as (1 D), or a salt, ester, metabolite or derivative thereof, wherein R1 comprise a compound selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof; R2 comprise a compound selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof; R4 comprises CH 2 OR6, COOR6 wherein R6 is selected
  • R7 comprises CH 3 , CH 2 OH, CHO, COOH, COOalkyl, COOaryl, COO-heterocyclic, COO-heteroaryl, CH 2 Oaryl, CH 2 O- heterocyclic, CH 2 O- heteroaryl, alkyls group, acetyl group or a derivative thereof.
  • R1 represents a compound comprising a sugar moiety comprising at least two compounds selected from, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R1 represents a compound comprising a sugar moiety comprising at least one compound selected from, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R2 represents a compound comprising a sugar moiety comprising at least one compound selected from, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R2 represents a compound comprising a sugar moiety or a compound which comprises at least two compounds selected from, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R4 comprises CH 2 OR6, COOR6 wherein R6 is a sugar moiety which comprises at least one compound selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R6 is a sugar moiety which comprises at least one compound selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R4 comprises CH 2 OR6, COOR6 wherein R6 is a sugar moiety which comprises at least two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R6 is a sugar moiety which comprises at least two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
  • R4 comprises CH 2 OR6, COOR6 wherein R6 is a sugar moiety which comprises at least two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, or alkyl; In an embodiment, R4 comprises CH 2 OR6, COOR6 wherein R6 is a sugar moiety which comprises at least two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, dibenzoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof; In an embodiment, R4 comprises CH 2 OR6, COOR6 wherein at least two of R1 , R2 and R6 comprise the compound selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl
  • R5 comprises 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 derivative thereof, or the combination thereof.
  • R5 comprises a compound capable of performing the function of the sugar moiety.
  • the R5 comprises a H.
  • R4 represents H or OH or CH 3 .
  • position 24 of the compound comprise CH 3 or CH 2 OH
  • positions 23, 24, 25, 26, 29, 30 of the compound independently comprise CH 3 ,
  • R5 comprises a sugar moiety comprising L-glucose, D-galactose, L- rhamnose, or/and L-arabinose.
  • R1 and R2 independently comprise an angeloyl group;
  • R1 is a sugar moiety or rhamnose which comprise two angeloyl groups.
  • R3 represents H or OH;
  • the compounds can be isolated from natural sources or synthesized.
  • 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.
  • 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 a method of inhibiting tumor cell growth comprising administering to a subject, in need thereof, an appropriate amount of triterpenoidal saponins comprising two or more angeloyl groups or comprising the structure of Figures 1-3, 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 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.
  • compositions for medicament comprising any one of triterpenoid saponins with the following formula:
  • This invention provides a composition comprising the compounds as described above effective in inhibiting cancer growth.
  • the cancer includes but is not limited to bladder cancer, bone, cancer, skin cancer and ovarian cancer.
  • This invention also provides a composition for inhibiting venous insufficiency, particularly hemorrhoids or inhibition of leg swelling, or inhibiting cancer growth comprising any of compounds selected from the following compounds:
  • composition for inhibiting cancer growth comprising any of the compounds selected from the following:
  • A1 3-O-[ ⁇ -D-galactopyranosyl (1 ⁇ 2)]- ⁇ -L-arabinofuranosyl(1 ⁇ 3)- ⁇ -D-glucuronopyranosyl- 21-O-angeloyl,22-O-benzoyl-3 ⁇ , 15 ⁇ , 16 ⁇ , 21 ⁇ , 22 ⁇ , 28-hexahydroxyolean-12-ene
  • B1 3-O-[ ⁇ -D-galactopyranosyl (1 ⁇ 2)]- ⁇ -L-arabinofuranosyl(1 ⁇ 3)- ⁇ -D- glucuronopyranosyl-21-O-(3-angeloyl, 4-benzoyl)- ⁇ -L-rhamnophyranosyl-22-O-acetyl- 3 ⁇ ,16 ⁇ , 21 ⁇ , 22 ⁇ , 28-pentahydroxyolean-12-ene
  • composition for inhibiting cancer growth comprising any of the compounds selected from the following:
  • Triterpenoid saponins with the characteristic structures mentioned above in this invention can be used to inhibit venous insufficiency, particularly hemorrhoids or inhibit leg swelling
  • Triterpenoid saponins with the characteristic structures mentioned above in this invention can be used to reduce or inhibit cancer growth.
  • 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.
  • Triterpenoid saponins with the characteristic structures mentioned above in this invention can be used to affect cell membrane structure and adhesion process. In an embodiment, it provides a method of binding with and adhesion proteins to blocks the migration, metastasis of cancer cells, and growth of cancers.
  • the compound is a triterpenoidal saponin or sapongenin, wherein the triterpenoidal saponin comprises at least any one or two of an angeloyl group, tigloyl group, or senecioyl group, or their combinations thereof at carbon 21 and/or 22, or 28, directly attached to the sapogenin or attached to a sugar moiety can be used to to treat varicose vein disease, inhibit venous insufficiency, particularly hemorrhoids or inhibit leg swelling, reduce or inhibit cancer growth.
  • the compound is a five ring triterpene saponin comprising at least two angeloyl groups, tigloyl group, or senecioyl group, or their combinations thereof and a sugar moiety.
  • the angeloyl groups are attached to a side chain at the end of the five rings and a sugar moiety is attached to a side chain of the ring at the other end of the five rings.
  • the compound comprises at least two angeloyl groups, a tigloyl group, or a senecioyl group, or combinations thereof and a sugar moiety.
  • the angeloyl groups and the sugar moiety are attached to the side chains of the backbone of the compound respectively.
  • the angeloyl can be replaced by a functional group which functions as an angeloyl group.
  • a sugar moiety or chain is at C3 or other positions, comprising 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 preferably D- glucose, D-galactose, L-rhamnose, L-arabinose, alduronic acids of D- glucuronic acid or D-galacturonic acid, or their combinations thereof, or their derivatives thereof.
  • CH 3 or CH 2 OH or COOH or acetyl group may attach at C 23-30 independently.
  • the activities of a saponin compound for regulating or inhibiting tumor cell growth are based on or attributed to its structure that has the functional group(s) such as angeloyl group, tigloyl group, senecioyl group or acetyl group, or their combinations thereof.
  • the compounds Y, Y1 , Y2, Y8, Y9 and Y10 which all have two angeloyl groups and, therefore, inhibited the growth of ovarian cancer cells (See Figure 5).
  • the compound (X) and Escin with single angeloyl groups showed weaker anticancer activity and hemolytic activity compared with the compounds with two angeloyl groups (See Figure 5, 6 and 7).
  • the compound without angeloyl groups has no anticancer and hemolytic activies (See
  • the compound with two angeloyl groups have stronger potency than the one with one angeloyl for 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 and peripheral vascular disorders.
  • This invention provides a composition comprising the compounds with the structure of:
  • R1 and R2 comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein the R1 and R2 comprise angeloyl groups.
  • R1 and R2 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • R1 and R2 comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein the R1 and R2 comprise angeloyl groups.
  • R1 and R2 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • the compound further comprises a sugar moiety.
  • the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
  • 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.
  • the R1 or R 2 may be attached in other position of the structure.
  • 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.
  • R1 , R2 and R3 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • At least one of R1 , R2 and R3 comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • the compound comprises a sugar moiety.
  • the sugar moiety is attached at one end of structure (d), opposite to R1 , R2 and R3.
  • the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
  • 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.
  • 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.
  • the R1 , R 2 and R3 may be attached in other position of the structure.
  • 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.
  • At least one of the side bonds comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • the compound comprises a sugar moiety.
  • the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
  • 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.
  • 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.
  • 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 triterpene comprise the following structure has anti-cancer or inhibiting virus activities.
  • 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.
  • R1 , R2 and R3 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • At least one of R1 , R2 and R3 comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative thereof.
  • R5 comprises a sugar moiety, wherein the sugar moiety comprises of glucose, galactose or arabinose or alduronic acid or combination thereof.
  • 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.
  • 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.
  • the R1 , R 2 and R3 may be attached in other position of the structure.
  • 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.
  • At least one of the side bonds comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acid with carbon 2-6 or derivative 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 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.
  • a compound or sapongenin comprises the structure (d) or (e) has anti-cancer or inhibiting virus activities.
  • a composition for 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.
  • the side chains are at alternative carbon in cis position.
  • the side chains are at alternative carbon in trans position.
  • the side chains are in non-adjacent carbon cis or trans position.
  • the side chains comprise a functional group capable of performing the function of angeloyl group.
  • This invention provides a composition regulating the protein on the surface of the cell or alters the functional properties of intracellular membranes.
  • the compounds and compositions provided in this invention can regulate the water passing through the cell wall to soften the skin or improve the skin structure.
  • 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, 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
  • This invention provides a composition for AntiMS, antianeurysm, 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, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, and venotonic treatment.
  • a composition comprising an effective amount of the compound of any one of YO, Y1 , Y2, Y(Y3),Y7, Y8, Y9, Y10, or a salt, ester, metabolite or derivative thereof as a medicament 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.
  • This composition can be administered orally or in a particular embodiment, it can be administered through intraperitoneal (I.P.) > intravenous (I.V.) injection or intravenous drip.
  • the medicine can be administered with glucose solution or NaCI solution.
  • the administration of the medicine can be as intravenous injection or intravenous drip.
  • Example 1 Intravenous drip: 0.05-0.2mg/kg medicine dissolved in 250ml of 10% glucose solution or in 250ml of 0.9% NaCI solution.
  • Example 2 Intravenous injection: 0.05-0.2mg/kg/day medicine dissolved in 10-2OmI of 10% glucose solution or of 0.9% NaCI solution. Course of treatment: 7-10 days.
  • Example 3 Intravenous drip: 0.1-0.2mg/kg/day medicine dissolved in 250ml of 10% glucose solution or in 250ml of 0.9% NaCI solution. Course of treatment: 7-10 days.
  • Example 4 Intravenous injection: 0.1-0.2mg/kg/day medicine dissolved in 10-2OmI of 10% glucose solution or of 0.9% NaCI solution. Course of treatment: 7-10 days.
  • Example 5 Intraperitoneal (I. P.): 2.5mg/kg/day medicine dissolved in 10% glucose solution or of 0.9% NaCI solution. Course of treatment: 7-10 days.
  • composition can be administered orally wherein the dosage of mammal is 1-10mg/Kg.
  • composition can be administered orally wherein the dosage is 10-30mg/Kg.
  • composition can be administered orally wherein the dosage is 30-60mg/Kg.
  • composition can be administered orally wherein the dosage is 60-90mg/Kg.
  • composition can be administered intravenous injection or intravenous drip wherein the dosage of mammal is 0.01- 0.1 mg/Kg.
  • the composition can be administered intravenous injection or intravenous drip wherein the dosage is 0.1-0.2mg/Kg.
  • the composition can be administered intravenous injection or intravenous drip wherein the dosage is 0.2 - 0.4mg/Kg,
  • composition can be administered intravenous injection or intravenous drip wherein the dosage is 0.4 - 0.6 mg/Kg.
  • composition can be administered intraperitoneal (I. P.) wherein the dosage of mammal is 1-3mg/Kg.
  • composition can be administered intraperitoneal (I. P.) wherein the dosage is 3-5mg/Kg.
  • composition can be administered intraperitoneal (I. P.) wherein the dosage is 4-6mg/Kg.
  • composition can be administered intraperitoneal (I. P.) wherein the dosage is 6-
  • This invention provides a method of treating a mammal for treating cancers comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a composition comprises the molecular formula or compound in this invention.
  • 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.
  • the compounds comprise Xanifolia YO, Y1 , Y2, Y, Y7, Y8, Y9, Y10, or a salt, ester, metabolite or derivative thereof. See experiments results in Figure 4-6, Figure 11-23 and Figure 37-38.
  • This invention describes a method interacting or regulating the protein on the surface of a cell or altering the functional properties of intracellular membranes or regulating the fluid passage through the cell wall to kill the cancer cells.
  • the method comprising administering contacting an effective amount of compound selected from formula (1 ), (1A), (1B), (1C), (1 D) preferable XanifoliaYO, Y, Y1 , Y2, Y7, Y8, Y9, Y10.
  • the compound select from Xanifolia YO, Y, Y1 , Y2, Y7, Y8, Y9, and Y10 interact with the protein in the membrane and open up the channel for water or solute particle.
  • the cell takes in water or solute particle and bursts.
  • the components of the compound select from XanifoliaYO, Y, Y1 , Y2, Y7,
  • Y8, Y9, and Y10 combine with the protein in the membrane and open up the channel for water or solute particle.
  • the cell takes in water or solute particle and bursts.
  • One or more aquaporin AQPs 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10 in the cancer cell membrane is overexpressed. So as providing more chance react with Xanifolia compound. Water or ion particle pass through the cell membrane the cancer cells
  • the compound select from XanifoliaYO, Y, Y1 , Y2, Y7, Y8, Y9, and Y10 dilute the solution outside the cancer to make more water pass in the cell.
  • the overexpress of Aquaporin of AQPs 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 provide more channel for water or ion particle which causes cancer cell die.
  • This invention provides a method of inhibiting cancer growth by destroys the cancer cell wherein aquaporin is overexpressed; 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.
  • the cancer is ovarian cancer.
  • This invention provides a method of treating a mammal for treating cancers comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a composition comprises the molecular formula or compound in this invention.
  • 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.
  • the compounds comprise Xanifolia YO, Y1 , Y2, Y, Y7, Y8, Y9, Y10, or a salt, ester, metabolite or derivative thereof.
  • Alkenyl means unsaturated linear or branched structures and combinations thereof, having 1-7 carbon atoms, one or more double bonds therein.
  • alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl.
  • An aryl is a functional group of organic molecule derived from carbocyclic aromatic compound such as benzene, a 6-14 membered carbocyclic aromatic ring system comprising 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 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, wherein there is a double bond between the carbon and oxygen.
  • the names of acyl groups typically end in -yl, such as formyl, acetyl, propionyl, butyryl and benzoyl.
  • Benzoyl is one of acyls, and can be represented as C 6 H 5 CO-R, obtained from benzoic acid by the removal of the carboxyl.
  • Heterocyclic compound a compound containing a non-aromatic heterocyclic ring which refers to a 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 heteroaryl , wherein said heterocyclic comprises pyrrolidinyl , pipyrazinyl , morpholinyl, trahydrofuranyl, imidazolinyl, thiomorpholinyl, and the like.
  • Alkanoyl is the general name for an organic functional group, represented by RCO-, where R represents hydrogen or an alkyl group.
  • RCO- organic functional group
  • alkanoyl is selected from acetyl , propionoyl, butyryl, isobutyryl, pentanoyl and hexanoyl.
  • Alkenoyl is alkenylcarbonyl in which alkenyl is defined above. Examples are pentenoyl (e.g. tigloyl) and hexenoyl (e.g. 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 refers 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.
  • 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, lsobutyryl is Synonym of 2-Methylpropanoyl Y and Y3 represent the same compound.
  • Xanifolia-Y is a novel triterpenoid saponin with a diangeloyl group attached at one end and carbohydrates or sugar moieties at another end of the triterpene structure.
  • the diangeloyl attached at C21 , C22 positions and carbohydrates or sugar moieties at C3 position of a triterpene structure.
  • the diangeloyl group is important for its activity.
  • the purified compound has been tested with 60 cancer cell lines. Test results show inhibition towards most cell lines tested with GI50 values ranging from 0.1 - 1 uM.
  • OVCAR3 cells cancer cells derived from ovary, are the most sensitive to Xanifolia-Y among cell lines tested in our early studies. We subsequently tested 10 additional human ovarian cancer cell lines and found all of them to be susceptible to inhibition by Xanifolia-Y with IC50 values ranging from 2-12 uM. See experiment 11.
  • the median survival time for tumor bearing mice with drug-treatment starting on day 4 after tumor inoculation is no death in 50 days; and tumor bearing mice with drug-treatment started on day 10 after tumor inoculation is half of the mice survive in 50 days.
  • the median survival time for tumor bearing mice with drug-treatment starting on day 4 after tumor inoculation is 58 days (extension of life span of 141 %); and tumor bearing mice with drug-treatment started on day 10 after tumor inoculation is 31 days (extension of life span of 29%).
  • Xanifolia-Y is capable of extending the life span of mammal bearing tumors. It is useful in treating ovarian cancer in humans.
  • ovarian cancer has the highest rate of mortality in women in the United States with an estimated 22,220 new cases in 2005 and over 16,000 deaths (NIH web info). The disease is often missed in diagnosis in the early stage due to asymptomatic and the lack of reliable diagnostic marker. As a result, most of the ovarian cancer patients being diagnosed are already at advanced stages.
  • the standard treatment of ovarian cancer is a combination of a platinum analogue with paclitaxel (McGuire et al., 1996; Ozols et al., 2003). Improved patients survival time was observed in patients with intraperitoneal administration of these agents (Armstrong et al., 2006). The peritoneal cavity is the principal site of disease in ovarian cancer. The improved efficacy of these agents could be due to a more direct interaction with cancer cells. However, the increase of median survival from 49.7 to 65.6 months is still far from satisfactory.
  • Xanifolia-Y is effective in prolonging mammal life span.
  • Mice were inoculated with human ovarian carcinoma (ES2) in the peritoneal cavity. Starting from the mid-way (time to mortality) point of tumor progression (considered as a late stage of disease in human), drug was then administered into the peritoneal cavity. It was found that Xanifolia-Y treatment is beneficial to tumor bearing mice by prolonging their life span. Depending on the stage of the disease progression, the sooner the start of the drug-treatment, the better the results are.
  • ES2 human ovarian carcinoma
  • Xanifolia-Y blocks the function of these adhesive molecules on cells. In an embodiment, Xanifolia-Y blocks the function of these adhesive molecules on carcinoma cells. In an embodiment, Xanifolia-Y blocks the function of these adhesive molecules on ovarian carcinoma cells. In an embodiment, Xanifolia-Y blocks the function of these adhesive molecules on the mesothelial cells. In an embodiment, Xanifolia-Y binds to the adhesive proteins (by masking) on the membrane and inhibits the interaction of adhesion proteins with their receptors. In an embodiment, Xanifolia-Y action on membrane affects adhesion proteins' function in membrane. The lost of adhesion activity of cancer cells is result from direct or indirect action of Xanifolia-Y on membrane proteins.
  • adhesion proteins are glycoproteins.
  • the carbohydrate moiety in adhesion proteins interact with carbohydrates from other molecules, such as saponin or Xanifolia-Y.
  • Xanifolia-Y has a trisaccharide at the C3 position and it was found that a loss of carbohydrates reduces its activity (Fig. 4D and 5C).
  • Our EM studies show that Xanifolia-Y affects membrane structure and makes holes. Damage to the membrane structure could alter adhesion protein's conformation and interfere with their binding with other molecules or even cause them to lose their anchorage on membrane.
  • These pits have the size from 8OA to 500A (in diameter).
  • the pits represent holes formed in the membrane.
  • the pits are arranged in a characteristic pattern with smaller pits (8OA in diameter) located in the periphery and the bigger ones (500A in diameter) in the center.
  • the bigger holes are resulted from fusing of the smaller holes (Fig. 25D).
  • Xanifolia-Y can be used for inhibiting cancers cell growth or treating cancers 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 cancer is preferably ovarian cancer.
  • carcinoma cells derived from ovary proved to be the most sensitive, a finding which is substantiated with more human ovarian cancer cell lines.
  • the results of animal studies with human tumor xenograft in mice show that it can extend the life span of mice bearing tumors.
  • the compounds of this application can extend the life span of a subject or mammal that bearing human cancer.
  • Xanifolia-Y is a new drug. It has effects on cell membrane, a target that differs from current anticancer drugs.
  • 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 method of inhibiting the growth, migration, metastasis of cancer by altering the characteristic of membrane of cancer cell, wherein the characteristic comprise adhesion protein; 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 YO, Y1 , Y2, Y, 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 invention provides a composition 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.
  • 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 15)
  • Xanifolia-Y extended the life span of tumor bearing mice. (See Experiments 7, 8, 9, and 10). 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 is blocking of the protein accessibility due to direct binding to Xanifolia-Y, In an embodiment, the interaction of Xanifolia-Y with membrane alter indirectly the adhesion protein's binding site(s).
  • Xanifolia-Y are cytotoxic to tumor cells, in an embodiment it kills ovarian cancer cells.
  • Our inventions show that Xanifolia-Y inhibits cancer cell growth and prolongs life-span of tumor bearing mice. Our studies also indicate that the sooner the drug- treatment, the longer the life-span of the tumor bearing animals is extended.
  • Xanifolia-Y also has an effect in blocking or inhibiting migration or metastasis. The delay of Xanifolia-Y- treatment allows more chances for cancer cells to metastasize to the mesothelium lining in the peritoneal cavity which resulted in more tumor growth and shorter life span. Adhesive molecules play an important role in cell migration and metastasis.
  • Xanifolia-Y inhibits cell attachment to culture flasks. Xanifolia-Y interferes with the function of the adhesive molecules. In embodiment Xanifolia-Y blocks the function of the adhesive molecules. In an embodiment, Xanifolia-Y binds directly to adhesive proteins. It is masking the adhesive proteins. In an embodiment, Xanifolia-Y indirectly alters membrane structure that cause changes in protein conformation, or locations and result in loss of adhesion process.
  • the pure compound Ys is an amorphous white powder, soluble in aqueous alcohol, i.e., methanol or ethanol, 50% acetonitrile and 100% pyridine.
  • D Inhibition analysis of Compound Ys with MTT assay
  • Figure 5A shows the inhibition activities of compound Y, Y8, Y9 and Y10 on the growth of ovarian cancer cells (OCAR-3).
  • Figure 27 shows the inhibition activities of compound Y's on the growth of ovarian cancer cells (OCAR-3)
  • the number of scans was 64.
  • the 2D data were zero-filled in t1 dimension to double the data points, multiplied by cosine-square-bell window functions in both t1 and t2 dimensions, and Fourier-transformed using software XWIN-NMR.
  • the final real matrix sizes of these 2D spectra are 2048x256 and 2048x512 data points (F2 ⁇ F1 ) for HMQC and HMBC, respectively.
  • Mass spectral analysis The mass of samples was analyzed by (A) MALDI-TOF Mass Spectrometry and by (B) ESI-MS Mass spectrometry.
  • This invention provides a bioactive compound YO and the chemical name is: 3-O-[ ⁇ -D-galactopyranosyl(1 ⁇ 2)]- ⁇ -L-arabinofuranosyl(1 ⁇ 3)- ⁇ -D-glucuronopyranosyl-21- O-angeloyl, 22-O-(2-methylpropanoyl)-3 ⁇ , 15 ⁇ , 16 ⁇ , 21 ⁇ , 22 ⁇ , 28-hexahydroxyolean-12- ene,
  • Athymic Nu/Nu mice are divided into three groups (A, B and C) with four animals in each group.
  • mice of group A and B were transplanted intra-peritoneally with ES2 (human ovarian cancer) cells.
  • mice from B and C groups received drug (Xanifolia-Y, by i.p. route at dose of 5 mg/kg)
  • B and C groups animals received daily drug administration of Xanifolia-Y, by i.p. route at dose of 2.5 mg/kg.
  • mice were divided into three groups (A, D and E) with four animals in each group. • On day 0, all mice were transplanted intra-peritoneally with ES2 (human ovarian cancer) cells.
  • mice received a daily drug administration of Xanifolia-Y, via i.p. route for 9 days at dose of 2.5 mg/kg.
  • mice received daily drug administration of Xanifolia-Y, via i.p. route for 10 days at dose of 2.5 mg/kg.
  • Group A Mice implanted with tumor and no drug. All died within 24 days; Group D, Mice implanted with tumor and were given drug 9 times from 4th day. All survived; Group E Mice implanted with tumor and were given drug 10 times from 10th day. Half the number of mice survived. Also See Figure 22
  • Experiment 9 Animal Study • Athymic Nu/Nu mice (2-3 months old) were transplanted sc with ES2 (human ovarian cancer) cells.
  • mice were divided into two groups (H and J) with two animals in each group.
  • mice On days 1-5, and 8-10 mice received daily drug administration of Xanifolia- Y, by i.p. route at dose of 2.5 mg/kg.
  • Group H Mice received drug-treatment, tumor size is 10 mm in 10 days
  • Group J Mice received no drug-treatment, tumor size is 18 mm in 10 days The tumor size is 45% smaller in mice with drug than the mice with no drug in 10 days period. See Figure 23
  • Athymic Nu/Nu mice (5-6 weeks old) are divided into three groups (O, P and Q) with 5-6 animals in each group.
  • mice On day 0, all mice were transplanted intra-peritoneally with ES2 (human ovarian cancer) cells. • Group O: animals received no drug-treatment.
  • Group P On days 4-8, 11-15, 18-22, 25-29, 32-36,39-43, animals received daily drug administration of Xanifolia-Y, by i.p. route at dosage of 2.5 mg/kg • Group Q: On days 10-15, 18-22, 25-29, 32-36, 39-43, animals received daily drug administration of Xanifolia-Y, by i.p. route at dosage of 2.5 mg/kg. Result:
  • the median survival time of tumor bearing mice without drug-treatment is 24 days.
  • the median survival time of tumor bearing mice with drug-treatment starting on day 4 after tumor inoculation is 58 days (extension of life span of 141 %); and
  • the median survival time of tumor bearing mice with drug-treatment started on day 10 after tumor inoculation is 31 days (extension of life span of 29%). See Figure 28
  • ovarian carcinoma cell lines are among the sensitive cells studied, we further investigated if other ovarian carcinoma cell lines are also susceptible to Xanifolia-Y.
  • Majority of ovarian cancers arise from the surface epithelium of ovary, most of them belong to the histological subtypes of clear cell and serous carcinoma.
  • the inhibition activity exerted by Xanifolia-Y was determined with MTT assay.
  • the following table shows the IC50 values of Xanifolia-Y on these cell lines. Results: Table 2. IC50 values of human ovarian carcinoma determined by MTT assay.
  • IC50 values of Xanifolia-Y in these cell-lines are ranging from 2 to 10 uM. These studies show that the effective concentration of Xanifolia-Y is in the micro-molar range which is comparable to those of other anti-cancer drugs.
  • Xanifolia-Y on membrane structure, the morphology of cell membrane treated with Xanifolia-Y was examined with EM.
  • K562 cells were treated with 5 uM of Xanifolia-Y for 60 min.
  • Solvent DMSO and AKOH-Y (a derivative of Xanifolia-Y without the angeloyl group and it has no activity) served as controls.
  • Cells were negative stained with 1 % UAc and subsequently examined with EM.
  • Figure 25 show that patches of pits were found in the membrane of Xanifolia-Y treated cells (Fig. 25B) but not in cells treated with the DMSO (Fig. 25A) or AKOH-Y (Fig. 25C) controls. These pits have the size from 8OA to 500A (in diameter). The pits represent holes formed in the membrane. The pits are arranged in a characteristic pattern with smaller pits (8OA in diameter) located in the periphery and the bigger ones (500A in diameter) in the center. The bigger holes are resulted from fusing of the smaller holes (Fig. 25D).
  • ES2 or Hey ⁇ A cells were plated in T25 flasks with medium containing 5 ug/ml of Xanifolia-Y. Cultures were incubated for 5 hours. Attached cells were removed from flasks by trypsinization and the amounts were counted. Compare to no drug controls, 86 ⁇ 4 % of ES2 cells and 67 ⁇ 8 % of Hey ⁇ A cells were found attached to flasks under this condition. At 5 ug/ml Xanifolia-Y, over 90% of unattached cells are alive as determined by the trypan Blue exclusion assay and by their ability to re-attach to flasks when plating in medium without Xanifolia-Y.
  • ES2 cells were exposed to (i) Xaniffolia-Y with concentrations of 40, 20, 10, 5, 2.5, and 1.25 ug/ml; or (ii) Paclitaxel with concentrations of 10, 5, 2.5, 1.25, 0.62 and 0.031 ng/ml; or (iii) Combined Xanifolia-Y and Paclitaxel with concentrations of each drug in same order (for example, 40 ug/ml Y plus 10 ng/ml T; 20 ug/ml Y plus 5 ng/ml T, etc.). Cells growth under these conditions was determined by the MTT assay.
  • the IC50 for Xanifolia-Y and Paclitaxel is 5ug/ml and 1.25 ng/ml, respectively. Additive effect was observed when both drugs were used, because in this case, the IC50 value for Paclitaxel (0.625 ng/ml) and for Xanifolia-Y (2.5 ug/ml) is less than those when they are used singly. See Figure 26.
  • Results The following figure shows the results of Western blot.
  • Aquaporin-1 (indicated with an arrow) was observed in OVCAR3 cells but was minimally detected in HeLa cells.
  • OVCAR3 cells Based on same amounts of protein loading into gel, it was found that OVCAR3 cells have higher concentration of Aquaporin-1 than in HeIa cells. Since OVCAR3 cells are more sensitive to Xanifolia-Y and it has a higher concentration of

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Abstract

La présente invention concerne une méthode visant à traiter le cancer en bloquant la migration, la métastase de cellules cancéreuses ou le développement de cancers tels que le cancer du sein, le cancer des leucocytes, le cancer du foie, le cancer des ovaires, le cancer de la vessie, le cancer de la prostate, le cancer de la peau, le cancer des os, le cancer du cerveau, la leucémie, le cancer du poumon, le cancer du côlon, le cancer du système nerveux central, le mélanome, le cancer du rein ou le cancer de l'utérus. Cette invention concerne également des utilisations de compositions renfermant une saponine triterpénoïdale, un triterpénoïde, un composé triterpénoïdal ou une sapongénine, contenant au moins deux groupes latéraux sélectionnés dans le groupe comprenant des groupes angéloyle, des groupes tigloyle et des groupes sénécioyle, lesdits groupes latéraux étant fixés au carbone 21, 22 et/ou 28 d'une saponine triterpénoïdale, d'un triterpénoïde, d'un composé triterpénoïdal ou d'autres squelettes de sapongénine.
PCT/US2007/077273 2003-10-09 2007-08-30 Composés antitumoraux servant à inhiber le développement du cancer WO2008028060A2 (fr)

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CN200780040744.4A CN101553497B (zh) 2006-09-01 2007-08-30 能抑止癌细胞生长的抗肿瘤化合物
EP07841638A EP2061798A4 (fr) 2006-09-01 2007-08-30 Composés antitumoraux servant à inhiber le développement du cancer
CA002676791A CA2676791A1 (fr) 2007-02-16 2008-02-15 Blocage de la migration ou de la metastase des cellules cancereuses par la modification de proteines d'adhesion et utilisations de nouveaux composes associes
EP08725693A EP2121715A4 (fr) 2007-02-16 2008-02-15 Blocage de la migration ou de la metastase des cellules cancereuses par la modification de proteines d'adhesion et utilisations de nouveaux composes associes
JP2009550096A JP2010519219A (ja) 2007-02-16 2008-02-15 接着タンパク質に影響を及ぼすことによる癌細胞の移動または転移の遮断およびその新規化合物の使用
PCT/US2008/002086 WO2008133766A1 (fr) 2007-02-16 2008-02-15 Blocage de la migration ou de la metastase des cellules cancereuses par la modification de proteines d'adhesion et utilisations de nouveaux composes associes
AU2008244648A AU2008244648A1 (en) 2007-02-16 2008-02-15 Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof
SG2012011029A SG178795A1 (en) 2007-02-16 2008-02-15 Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof
CN200880012065A CN101772511A (zh) 2007-02-16 2008-02-15 通过影响粘连蛋白质表达阻止癌细胞的转移和新化合物及其应用
AU2009200988A AU2009200988B2 (en) 2003-10-09 2009-03-10 Anti-tumor compounds for inhibiting cancer growth
US12/856,322 US8586719B2 (en) 2005-04-27 2010-08-13 Triterpenes for modulating gene expression and cell membrane, and as antiprotozoal agents
US13/841,053 US9382285B2 (en) 2004-09-07 2013-03-15 Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells
US15/181,631 US10213451B2 (en) 2004-09-07 2016-06-14 Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells
US16/285,634 US11046724B2 (en) 2004-09-07 2019-02-26 Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells
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US8586719B2 (en) 2005-04-27 2013-11-19 Pacific Arrow Limited Triterpenes for modulating gene expression and cell membrane, and as antiprotozoal agents
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