CN101772511A - Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof - Google Patents

Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof Download PDF

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CN101772511A
CN101772511A CN200880012065A CN200880012065A CN101772511A CN 101772511 A CN101772511 A CN 101772511A CN 200880012065 A CN200880012065 A CN 200880012065A CN 200880012065 A CN200880012065 A CN 200880012065A CN 101772511 A CN101772511 A CN 101772511A
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acyl group
cancer
angiogenin
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pyrans
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陈沛光
麦美送
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Pacific Arrow Ltd
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Pacific Arrow Ltd
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Priority claimed from US11/683,198 external-priority patent/US8614197B2/en
Priority claimed from PCT/US2007/077273 external-priority patent/WO2008028060A2/en
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Abstract

This invention provides methods, processes, compounds and compositions for modulating the gene expression or secretion of adhesion proteins or their receptors to cure disease, wherein the modulating comprises positive and negative regulating; wherein comprises inhibiting cancer growth, wherein the adhesion proteins or receptors comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK; wherein the methods, processes, compounds and compositions are also for anti-angiogenesis; 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.

Description

Express transfer and new compound and the application thereof that stops cancer cells by influencing Fibronectin matter
This patent requires to patent application form (PCT/US2007/077273, on August 30th, 2007 submitted, U.S.Serial NO.60/890.380, on February 16th, 2007 submitted, U.S.Serial NO.60/974,705, submitted No.11/683 on July 3rd, 2007 with U.S.Serial, 198, on March 7th, 2007 submitted) in desired right or right of priority, above-mentioned four applications for patent require to obtain U.S. Patent application book (U.S.Serial Nos.60/795 again, 417, April 27 in 2006 submitted, 60/841,727, on September 1st, 2006 submitted and 60/890,380, on February 16th, 2007 submitted) and and international patent application book (NO.PCT/US2006/016158, on April 27th, 2006 submitted) in desired right or right of priority, these three U.S. Patent application books and international patent application book require to obtain the right or the right of priority of following application for patent again: (1) U.S. Patent application book (U.S.Serial NO.11/289,142, submitted the NO.11/267 with U.S.Serial on November 28th, 2005, on November 4th, 523,2005 submitted), (2) international patent application book (NO.PCT/US2005/031900, on September 7th, 2005 submitted, and this application book requires to obtain U.S. Patent application book, U.S.Serial NO.60/617.379 again, on October 8th, 2004 submitted, U.S.Serial NO.60/613 submitted the NO.60/607 with U.S.Serial on September 27th, 811,2004, desired right or right of priority in submitting on September 7th, 858,2004.), (3) U.S. Patent application book U.S.Serial NO.11/131 submitted on May 17th, 551,2005 and (4) U.S. Patent application book U.S.Serial NO.11/117, and on April 27th, 760,2005 submitted.Thereby, the content of the application for patent that these are being authorized thereby should include in the present patent application all sidedly.
Invention field
This patent provides can be by influencing gene in the expression of cell and the method and composition of cure diseases is characterized in that described method can alleviate the symptom of this disease.Under this certain situation, but the expression of this method suppressor gene, and in another case, this method can excite expression of gene again.
This patent provides the method and the process of cure diseases, and compound and composition, it is characterized in that described method and process, and compound and composition can be regulated expression of gene, regulate the secretion of Fibronectin matter and regulate their acceptor, thereby reach the purpose of cure diseases, comprising the growth that suppresses cancer.Here, Fibronectin matter and their acceptor comprise fibronectin (fibronectin), the albumen of integrin family (integrins family), myosin (Myosin), vitronectin (vitronectin), collagen protein (collagen), ln (laminin), glycosylation cell surface protein (Glycosylationcell surface proteins), saccharan albumen (polyglycans), calcium conglutination element (cadherin), heparin albumen (heparin), tough sticking element (tenascin), cell adhesion molecule CAM, adhesion molecule CD54, elastin (elastin) and FAK albumen.
Background of invention
Cancer metastasis is cancer of late stage cancer cells other positions from former zone-transfer to health.Cancer cells is peeled off away from former tumour and is sticked on the extracellular matrix, transfers to other positions of health by blood flow or lymphsystem.Fibronectin is playing crucial effects in cancer metastasis.
When cancer cells took place, the way of processing had the radiosurgery therapy, chemotherapy, radiotherapy, biotherapy, hormonotherapy, operation and laser-immunotherapy etc.But these methods usually can not stop the generation of cancer metastasis.
Summary
This patent provides a kind of anticancer method, it is characterized in that described method is to regulate the cancer cells adhesion and stops cancer metastasis, or anticancer growth, or anti-angiogenic rebirth, thereby reach anticancer purpose, wherein, Fibronectin matter and their acceptor comprise fibronectin (fibronectin), the albumen of integrin family (integrins family), myosin (Myosin), vitronectin (vitronectin), collagen protein (collagen), ln (laminin), glycosylation cell surface protein (Glycosylation cell surface proteins), saccharan albumen (polyglycans), calcium conglutination element (cadherin), heparin albumen (heparin), tough sticking element (tenascin), cell adhesion molecule CAM, adhesion molecule CD54, elastin (elastin) and FAK albumen.
This patent also provides a kind of anticancer method, it is characterized in that described method is to reduce the adhesion in the cell and stops cancer metastasis, or anticancer growth, or angiogenesis inhibitor, thereby reach anticancer purpose, wherein, Fibronectin matter and their acceptor comprise fibronectin, the protein of integrin family, myosin, vitronectin, collagen protein, ln, the glycosylation cell surface protein, saccharan albumen, the calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen.Under certain conditions, described method is to reduce the secretion of fibronectin.In another case, described method is to suppress the expression of Fibronectin, and here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.
This patent also provides a kind of anticancer method, it is characterized in that described method is by changing the growth of characteristic anticancer and the transfer of cancer cell membrane, comprising Fibronectin, cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer (CNS), melanoma, cervical cancer and uterus carcinoma etc.
The detailed description of figure
Fig. 1. cultivate back cancer cells (ES2) eccrine fiber together with Xanifolia-Y and be connected albumen and be suppressed.The fibronectin that is discharged in the substratum is measured by immunoblotting.A:Y is compounds X anifolia-Y (experiment F1 result); B:(tests F3 result); C:(tests F4 result).
Fig. 2. compounds X anifolia-Y suppresses the secretion (immunoblot experiment) of fibronectin.A: experiment F5 result; B: experiment F7 result; C: experiment F8 result; D: experiment F11 result; E: experiment F12 result; F: experiment F13 result; G: experiment F14B result; H: experiment F14C result.
Fig. 3. compounds X anifolia-Y suppresses the secretion (immunoblot experiment) of fibronectin.A: experiment F23 result; B: experiment F24 result; C: experiment F26 result; D: experiment F27 result; E: experiment F29 result; F: experiment F28 result.
Fig. 4. compounds X anifolia-Y suppresses the secretion (immunoblot experiment) of fibronectin.A: experiment F30 result; B: experiment F31 result; C: experiment F32 result; D: experiment F33A result; E: experiment F20 result.
Fig. 5. compounds X anifolia-Y increases (ANGPT2) synthetic quantity in the ES2 cell of angiopoietin-2 (Angiopoietin-2).
The detailed description of application
The invention provides the application of preparation heal with drugs disease or the method and composition of the symptom that palliates a disease, the method that it is characterized in that described treating disease or the symptom that palliates a disease is to reach by the expression with described composition regulatory gene. Here the expression of said regulatory gene is just comprising the adjusting of (positive), also comprises the adjusting of negative (negative). That is to say the expression of suppressor in some cases and expression two aspects of stimulated gene in another case.
The present invention also provides inhibition cancer cell to shift and growth, or the method and composition of anti-angiogenic generation, it is characterized in that described method achieves the above object by affecting gene expression on the one hand, Fibronectin or their acceptor reduce or expression or the secretion of inhibition Fibronectin achieve the above object by affecting on the other hand. Here said Fibronectin comprises albumen (integrinsfamily), myosin (Myosin), vitronectin (vitronectin), collagen (collagen), laminin (laminin), glycosylation cell surface protein (Glycosylation cellsurface proteins), polysaccharide albumen (polyglycans), calcium conglutination element (cadherin), heparin albumen (heparin), tough sticking element (tenascin), CAM CAM, adhesion molecule CD54, elastin laminin (elastin) and the FAK albumen of fibronectin (fibronectin), integrin family.
The present invention also provides inhibition cancer cell to shift and growth, or the method and composition of anti-angiogenic generation, it is characterized in that described method in some cases expression and the in another case expression of stimulated gene of suppressor.
The present invention also provides the method by the characteristic that changes cancer cell membrane to stop cancer metastasis and growth, or the method for angiogenesis inhibitor, described method also comprises by reducing Fibronectin or their acceptor and reaches and stop cancer metastasis and growth, or the purpose of angiogenesis inhibitor.Here said Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.
Expression, secretion or synthetic that the present invention also provides the preparation medicine to reduce cell adhesion protein are used process, compound and composition.Here said Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Here said method comprises inhibition of gene expression, reduces the secretion of fibronectin, stops the transfer and the growth of cancer cells, or angiogenesis inhibitor.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer (CNS), melanoma, cervical cancer and uterus carcinoma etc.
The method that the present invention also provides the application of preparation medicine to change the characteristic of cancer cell membrane, process, compound and composition is characterized in that described application is to achieve the above object by the secretion that changes Fibronectin.Here said Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Embody under the situation of the present invention one, described method, process, compound and composition comprise expression, secretion or the synthetic that stops or suppress Fibronectin.Embody under the situation of the present invention one, described method, process, compound and composition are to react with Fibronectin.Under a kind of embodiment situation of the present invention, described method, process, compound and composition comprise transfer and the growth that stops cancer cells, or angiogenesis inhibitor.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.Fibronectin can help the cancer cells adhesion, invasion and transfer.Cancer described here is meant ovarian cancer.Reduce the transfer that Fibronectin just can lower cancer cells.Fibronectin is a key factor in the epithelium ovarian cancer biology.Reduce the transfer that fibronectin just can lower cancer cells.The present invention also provides inhibition Fibronectin excretory method and composition, and said here Fibronectin is meant fibronectin.Suppress transfer and growth that the Fibronectin secretion just can stop cancer cells.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
The present invention also provides a kind of composition of can the anticancer growth and shifting, and it is characterized in that described composition is the characteristic that can change cancer cell membrane.The characteristic of cancer cell membrane described here is the characteristic of Fibronectin, and it comprises the adhesion ability of proteic secretion and cell.Here said Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.The method that achieves the above object is with compounds X anifolia Y0, Y1, and Y2, Y, Y7, Y8, Y9, Y10, ACH-Y or their salt, the ester class, meta-bolites is handled cancer cells, and adjusts the used dosage of these compounds.Described here compound is to select the compound with certain structural formula that provides from this patent.
The application of sticking characteristic that the present invention also provides the preparation medicine can change cancer cell membrane is characterized in that described application comprises the secretion that reduces the ability of sticking and lower fibronectin.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.The method that achieves the above object is the compounds X anifolia Y0 with doses, Y1, and Y2, Y, Y7, Y8, Y9, Y10, ACH-Y or their salt, the ester class, meta-bolites is handled cancer cells, and adjusts the used dosage of these compounds.Described here compound is to select the compound with certain structural formula that provides from this patent.One of method of these compound effects cancer cells is the growth and the transfer of anticancer.These compounds have following structural formula: (1A), and (1B), (1C) and (1D).Compound contains the female ring of triterpene, two angeloyl groups and sugar chain.Described here compound is from compounds X anifolia (x), selects in escin or the Aescin.Described here compound, or to X1, select to X and A1 from the compd A that this patent provides.In another case, described here compound is selected to Z7A from the compound Z1 that this patent provides.
The characteristic of sticking that the present invention also provides composition can change cancer cell membrane, said here cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
The present invention also provides and can prepare application and the composition that medicine minimizing Fibronectin reaches the treatment disease, it is characterized in that the disease of described medical treatment comprises that suppressing cancer grows, and it is swollen to alleviate leg, chronic venous insufficiency, the tip oedema, anti-lipid, chronic venous disease, varix, varix symptom, venous stasis, eliminate the phlegm, the peripheral vessel disorder, the brain organ is twitched, the cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling alleviates the skelagia sign, itch, the sign that eases the pain, thrombosis; Prevent and treat stomach ulcer and antispastic etc.When these diseases of treatment, regulate the consumption of composition simultaneously.
The method that this minimizing Fibronectin reaches the treatment disease comprises interaction with these compositions and Fibronectin, and said here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.
The method of this treatment disease also comprises the adhesion ability that reduces Fibronectin, and said here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.
This method for preparing the pharmacological agent disease also comprises the secretion of regulating Fibronectin, and said here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.The method of this treatment disease also comprises the secretion that stops Fibronectin, and said here Fibronectin is a fibronectin.Described here compound is to select the compound with certain structural formula that provides from this patent, and adjusts the used dosage of these compounds.
The method that achieves the above object is the compounds X anifoliaY0 that this patent with doses provides, Y1, and Y2, Y, Y7, Y8, Y9, Y10, ACH-Y or their salt, the ester class, meta-bolites is handled cancer cells, and adjusts the used dosage of these compounds.Described here compound from A to X and A1 in the X1 compound, select.Under a kind of embodiment situation of the present invention, described here compound is selected to Z7A from the compound Z1 that this patent provides.These compounds may have following structural formula: (1A), and (1B), (1C) and (1D).
The present invention also provides application and the composition that reaches the medicine of treatment disease by the characteristic that changes Fibronectin, and the characteristic that it is characterized in that described Fibronectin is its adhesive properties, described method comprise reduce Fibronectin secretion, the disease of medical treatment comprises that suppressing cancer grows, and it is swollen to alleviate leg, chronic venous insufficiency, the tip oedema, anti-lipid, chronic venous disease, varix, varix symptom, venous stasis, eliminate the phlegm, the peripheral vessel disorder, the brain organ is twitched, the cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling alleviates the skelagia sign, itch, the sign that eases the pain, thrombosis; Prevent and treat stomach ulcer and antispastic etc.When these diseases of treatment, regulate the consumption of composition simultaneously.Here said Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Described here compound is to select the compound with certain structural formula that provides from this patent, and adjusts the used dosage of these compounds.
The present invention also provides a kind of extraction and purifying, or synthetic has the compound (1A) of following structural formula:
Figure GSB00000006033200061
Its salt, ester, meta-bolites or derivative.Wherein R1 is H, hydroxyl, O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the saturated acyl group that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group; the O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof.Wherein R2 is H, hydroxyl, O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkanoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group; the O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof.R4 is CH 2R6 or COR6, wherein R6 is a chemical group, contains hydroxyl; the O-angeloyl groups, O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group; the O-alkyl, the two benzoyls of O-, O-benzoyl; the O-alkanoyl, O-alkenoyl, the saturated acyl group that O-phenmethyl alkyl replaces; the O-aromatic base, O-acyl group, O-heterogeneous ring compound; O-heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof.R3 is H or OH.R8 is H or OH, particularly OH.R5 is hydrogen or sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid (alduronic acid), glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.R9, R10, R11, R12, R13, R14 and R15 are connected group a: CH in the following group separately 3, CH 2OH, CHO, COOH, COO-alkyl, COO-alkyl, COO-heterogeneous ring compound, COO-heterocyclic aromatic compounds, CH 2The O-aromatic base, CH 2The O-heterogeneous ring compound, CH 2The O-heterocyclic aromatic compounds, alkylate, hydroxyl, acetyl compounds, particularly CH 3At R1, among R2 and the R6, have at least two to contain following group: the O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the saturated acyl group that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group; the O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof.Or at R1, among R2 and the R4, at least one sugar chain by two in the following group substitute: angeloyl groups; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, alkanoyl; alkenoyl, the alkanoyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof.
Here R4 is CH 2R6; R1 and R2 contain an angeloyl groups separately, or at R1, among R2 and the R6, have at least two to be the O-angeloyl groups, or at R1, a sugar chain that contains two angeloyl groups are arranged among R2 and the R6; R5 is a sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.But with glucose, semi-lactosi and Ah Bai sugar is for well.Under a kind of embodiment situation of the present invention, R5 is that sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, pectinose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.
The compound that described here method is to use this patent to provide is characterized in that described compound is to elect from the compound with following structural formula:
1) a kind of extraction and purifying, or synthetic has the compound of structural formula Xanifolia (Y):
Figure GSB00000006033200071
The title of this compound is 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21; acyl group-3 β returns in the two parties of 22-O-; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
2) a kind of extraction and purifying, or synthetic has the compound of structural formula Xanifolia (Y1):
Figure GSB00000006033200072
The title of this compound is 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O (3; acyl group is returned by the two parties of 4-)-α-L-rhamnosyl pyrans acyl group-22-O-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
3) a kind of extraction and purifying, or synthetic has the compound of structural formula Xanifolia (Y2):
Figure GSB00000006033200081
The title of this compound is 3-O-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21; acyl group-3 β returns in the two parties of 22-O-; 15 α; 16 α; 21 β; 22 α, 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
4) a kind of extraction and purifying, or synthetic has the compound of structural formula Xanifolia (Y8):
Figure GSB00000006033200082
The title of this compound is 3-O-[β-glucose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β, 16 α return in the two parties of 22-O-; 21 β; 22 α, 24 β, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
5) a kind of extraction and purifying, or synthetic has the compound of structural formula Xanifolia (Y9):
Figure GSB00000006033200083
The title of this compound is a 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28-O-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
6) a kind of extraction and purifying, or synthetic has structural formula Xanifolia (Y10) compound:
Figure GSB00000006033200091
The title of this compound is a 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21; acyl group-3 β, 16 α, 21 β return in the two parties of 22-O-; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
7) a kind of extraction and purifying, or synthetic has structural formula Xanifolia (YO) compound:
The title of this compound is 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group-22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
8) a kind of extraction and purifying, or synthetic has structural formula Xanifolia (X) compound:
Figure GSB00000006033200093
The title of this compound is 3-O-{[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyranoside butyl ester }-the 21-O-ethanoyl; acyl group-3 β returns in 22-O-party; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
9) a kind of extraction and purifying, or synthetic has structural formula Xanifolia (Y7) compound:
Figure GSB00000006033200094
The title of this compound is 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group-28-O-(2-first butyryl radicals)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
10) a kind of extraction and purifying, or synthetic has the compound of following structural formula (ACH-Y):
Figure GSB00000006033200101
In other cases, the method for use is the compound that provides with capital and interest, it is characterized in that described compound elects from following compound:
11) a kind of extraction and purifying, or synthetic has the compound of following structural formula:
Figure GSB00000006033200102
12) a kind of extraction and purifying, or synthetic has the compound of following structural formula:
Figure GSB00000006033200103
In other cases, the method for use is the compound that provides with capital and interest, it is characterized in that described compound is to extract and purifying, or synthetic has the compound of following structural formula:
Figure GSB00000006033200104
Wherein R1 and R2 are each O-ethanoyl or O-angeloyl groups naturally, R3 wherein, and R4, R5, R6 and R7 are hydrogen or hydroxyl.
Specifically, the compound of the be used in present method that provides has Xanifolia Y0 in this application, Y1, Y2, Y, Y7, Y8, Y9, Y10, Xanifolia (x), escin or Aescin, and its esters, ester class and meta-bolites.Also can (1B), (1C) and in the compound (1D) select from having structural formula (1A).These compounds have the female ring of triterpene, two angeloyl groups and sugar chain.
These compounds can also be from compounds X anifolia Y0, Y1, and Y2, Y, Y7, Y8 selects among Y9 and the Y10.Also can (1B), (1C) and in the compound (1D) select from having structural formula (1A).Also can be from Xanifolia (x), escin or Aescin are selected.Also can select to X1 to X and A1 from the compd A that this patent provides.Also can select to Z7 from the compound Z1 that this patent provides.These compounds have the female ring of triterpene, and the carbon 21 of female ring and 22 have insatiable hunger group, and 3 in carbon has sugar chain.
These compounds that this patent provides can reduce tackyness, suppress the ability of infectation of bacteria and the preferendum (tropism) of regulating cell.
Embody explanation at one, this patent provides medicinal application in the tackifying ability that reduces cell or virus, thereby stops virus and host's combination, and the virus of saying here is to comprise HIV.
The compound that the composition that this patent provides includes physiologically active be propose from natural phant or synthetic.Here said plant mainly is the plant of Sapindaceae, and there are 140-150 genus, 1400-2000 kind in this section.Compound is purified and biological activity determination (comprising that MTT measures) is asked for an interview international patent application book (PCT/US05/31900N0, on September 7th, 2005 submitted), U.S. Patent application book (U.S.SerialNo.11/289142, November 28 in 2005 and U.S.Serial No.11/131551, May 17 in 2005) thereby, the content of the application for patent that these are being authorized thereby should include in the present patent application all sidedly.
The composition that this patent provides contains triterpenoid saponin.This triterpenoid saponin contains triterpene; triterpenes or other sapogenins; one or more sugar chain; two angeloyl groups or at least two side chain compounds are made up of following group: the Radix Angelicae Sinensis acid amides; crotonamide (tigloyl) or senecio amide (senecioyl); and these two side chains will be bound up on triterpenoid saponin, and former (triperpenoidal is triperpenoid) and on the carbon 21 of the former female ring of other saponins and 22.Here the side chain of said saponin contains in the following group two at least: angeloyl groups, and along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl; alkanoyl; alkenoyl, the alkanoyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof.Here the sugar chain of said saponin contains one or more following sugar and uronic acid: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid (alduronic acid), glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.Glucuronic acid in this case, semi-lactosi and pectinose are the selections of the best in these sugar.
Patent disclosure of the present invention one composition, it is characterized in that composition contains a compound, few two side chains of its chemical structural formula are made up of following group: the Radix Angelicae Sinensis acid amides, crotonamide (tigloyl) or senecio amide (senecioyl), and these two side chains will be bound up on triterpenoid saponin, and former (triperpenoidal is triperpenoid) or on the former female ring of other saponin.These form composition or compound extracts or synthetic from plant.
The invention discloses the processing method of preparation above-claimed cpd, it is characterized in that described processing method is as follows: (1) uses the shell of the above-mentioned indicated plant of organic solvent lixiviate, branch is done leaf, kernel, root, bark, or plant shell, or their mixture gets the organic solvent extractive substance, it is characterized in that described organic solvent is ethanol or methyl alcohol; (2) collect the organic solvent extractive substance; (3) refluxing extraction gets extract for the second time; (4) reclaim organic solvent and must get extract for the third time; (5) dry and sterilize extract for the third time, the powdery crude extract; (6) usable highly effective liquid chromatography (HPLC) and quick-acting liquid chromatography (FPLC) with C18 silicagel column or other corresponding solid phase material, are separated into one or more component to powdered extract; (7) if use high performance liquid chromatography (HPLC) and quick-acting liquid chromatography (FPLC), detecting absorbing wavelength is that 207nm is to 500nm; (8) bioactive component is provided in evaluation from said components; (9) separate with quick-acting liquid chromatographies (FPLC) and the composition of the above-mentioned biologically active of purifying; (10) use high performance liquid chromatography (HPLC) to isolate the compound of biologically active again.
The invention discloses and measure saponin or the bioactive mtt assay of other compound, it is characterized in that described antitumour activity draws by the mtt assay check with 11 kinds of human cancer cells.Used cell is that 11 kinds of human body cells are: HTB-9 (bladder), HeLa-S3 (uterine neck), DU145 (prostate gland), H460 (lung), MCF-7 (mammary gland), k562 (white corpuscle), HCT116 (colon), HepG2 (liver), U20S (bone), T98G (brain), and OVCAR-3 (ovary).These 11 kinds of human body cells are to obtain from US mode DSMZ (American TypeCulture Collection).Cultivate: HeLa-S3 (uterine neck), DU145 (prostate gland), MCF-7 (mammary gland), HepG2 (liver) and T98G (brain) cell cultures are on MEN (Earle salt) substratum.HTB-9 (bladder), H460 (lung), 562 (white corpuscles) and OVCAR-3 (ovary) cultivate on the RPMI-1640 substratum, and other cell is on the McCoy-5A substratum.These substratum all will add 10% fetal bovine serum, glutamine and antibiotic.At CO 2Concentration is 5% interior cultivation of incubator.
MTT detects detection method and has adopted the method for Carmicheal et al.1987 substantially, and has done some changes.These cell cultures in the vesicle of the culture dish that 96 vesicles are arranged 24 hours; Every cave 10,000 HTB-9 (bladder), HeLa-S3 (uterine neck), H460 (lung), HCT116 (colon), T98G (brain), and the cell of OVCAR-3 (ovary); Every cave 1.5 ten thousand DU145 (prostate gland), MCF-7 (mammary gland), the cell of HepG2 (liver) and U20S (bone); Every cave 40,000 k562 (white corpuscle).Then, the sample of Lignum Xanthoceratis extract is put into the cave, cultivate 48 hours (liver and osteocarcinoma cell 72 hours, breast cancer cells 96 hours again.Then, MTT (0.5mg/ml) adds in each cave, cultivates 1 hour.The formazan that produces is dissolved in DMSO, uses ELISA reader (Dynatech, Model R700) to survey its O.D. value (TD) at 490nm then.Adding the preceding MTT O.D. value (TO) of sample also will measure.The percentage ratio (%G) of every kind of cell growth can be obtained by following formula
％G＝(TD-TO/TC-TO)x?100(1)
(TC is the O.D. value of control cells group)
When T0＞TD, then cell-specific toxic reaction (LC) value is:
％LC＝(TD-T0/T0)x?100(2)
Microarray (Microarray): the analysis of ES2 cell genetic expression after the process Y processing in microarray (Microarray) test.This patent has carried out microarray (Microarray) experiment in research genetic expression.Altogether 54676 genes are studied.
Cell training sample and drug treating: the ES2 cell inoculation is in the T-25 triangular flask, and 4.5 hundred ten thousand cells in each triangular flask were cultivated 24 hours.Nutrient solution changes into respectively and new contain xanifolia-Y (Y) or DMSO (contrast, D) nutrient solution was being cultivated 24 hours then.The results cultured cells is carried out the extraction of RNA.Three experiments have been carried out.
The extraction of RNA, coding, hybridization and data analysis: carry out the extraction of RNA with reagent and method that Qiagen RNeasy Kit. provides.Before carrying out next step experiment, usefulness Agilent BioAnalyzer and spectrophotometer (
Figure GSB00000006033200131
ND-1000RNA) detect the quality and quantity of RNA respectively.The total RNA from 20ng in two amplification cycles synthesizes the first and second cDNA bands with AffymetrixT7oligo (dT) primer and method.With MegaScript kit (Ambion) the cDNA reverse transcription, the biotin labeled cRNA that must increase.15.0 the biotin labeled cRNA fragment spectrophotometer of μ g (
Figure GSB00000006033200132
ND-1000RNA) detect its concentration once more.The cRNA fragment of hybridizing reagent Affymetrix spike-in and sign inserts human body U133 and adds 2.0
Figure GSB00000006033200133
Oligonucleotide arrays.(Affymetrix, Inc.Santa Clara CA) include 1,300 to the Affymetrix array, and special oligonucleotide characteristic more than 000 has been represented more than 38,500 important human body gene.Strepavidin is used in the hybridization 16 hours under 45 ℃ and revolution 60rpm of this array then, and R-phycoerythrin conjugate washs on AffymetrixFluidicis Station 450 and dyes.The antistreptavidin that single expansion is given with the vitamin H acyl groupization finishes.This array is used can be self-loading
Figure GSB00000006033200134
3000 with the focal argon laser scanner scanning.Scan image is analyzed with Affymetrix GCOS software (version 1.4) and is carried out quality control matrix record.Preferably the data of each genetic expression are calculated with dChip PM-only model bank or Plier operational method.
Data analysing method
Matched pair technique is compared as follows: handle vs contrast (Y vs D), the analysis Bioconductor package of R mathematical statistics of altered medicine vs contrast (YM/ACY-H vs D) and the processing altered medicine of vs (Y vs YM/ACH-Y) CEL file.Analyze the change gene that can obtain between a considerable number of different samples by Limma.Undressed data GCRMA method (the many array analysis of the robust) stdn of CEL file.Finish in Bioconductor ( Http:// www.bioconductor.org/).To unprocessed single augmentation data stdn, background is corrected and is summarized according to certain mathematical analysis model.The genetic expression value is each mark, each wafer (chip) with Log2-scaleExpress.Null hypothesis checks that genetic expression does not have marked difference between a pair of processing.Finish with LIMMA and Bioconductor.Estimate the variation of genetic expression with experience Bayes theorem (empirical Bayes).Done the comparison of high-grade vs inferior grade (High Grade vs.Low Grade).All gene expression datas are all checked with p value (0.05).
Unprocessed p value is adjusted with the Benjamnin-Hochberg method, with the appearance (FDR) of controlling false ratio.
Immunoblotting
In this patent, the special albumen that contains in the compound treatment that provided by this patent and the untreated cancer cells is provided the utilization immunoblotting.Said here here cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
Cancer cells is cultivated in the RPMI RPMI-1640, each T25 triangular flask 1.5 hundred ten thousand cell cultures 24 hours.(concentration is respectively 10,20,30,40 to the cancer cells of Pei Yanging, and 80ug/ml) the new substratum RPMI of the contrast DMSO of (Y) and 2.5ul (contrast D) cultivates with the compound that contains the desire examination more then.Cultivate after 24 hours, get the content (immunoblotting mensuration) that the part nutrient solution is measured fibronectin.Cell survival rate after measuring 24 hours with mtt assay.Cultured cells was cultivated 1 hour with the nutrient solution (5ml) of the RPMI that contains MTT.Generate among the DMSO that De Jia Za (formazan) is dissolved in 10ml and measure (MTT unit) at the 570nm wave band with OD.
The cell suspension that sticks together in 1ml SDS damping fluid (cell extract),
Immunoblotting: culture (0.6ml) and damping fluid SDS (0.2ml) mix, and cell extract boiled 3 minutes, put into sds gel then.Sample (80ul/lane) is put into 6-10%SDS gel electrophoresis (100volts) 2 hours.Albumen changes nitrocellulose membrane (100volts, 30 minutes) over to by electrophoresis.Digest cellulose film trace (blot) seals in the PBS that contains 5% skim-milk.Trace (blot) anti-hatching (and first antibody, mouse-anti-FN, specifically at human fibronectin, SIGMA F0916) and two anti-hatch (second antibody, the IgG AP conjugation of anti-mouse, Promega S3721).The immunity bands of a spectrum develop the color with BCIP/NBT developer system (Promega S3771).The bands of a spectrum image of immunoblotting is taken pictures (an every gel 3-5 photo) with digital camera, and the fluorescence intensity of bands of a spectrum is determined with " Image J " software.。
This patent provides the triterpenoid saponin that contains effective dose compound compositions, it is characterized in that described triterpenoid saponin compound is Xanifolia Y0, Y1, Y2, Y, Y7, Y8, Y9, Y10 or derivatives thereof.This composition can be regulated Fibronectin, reduces the secretion of Fibronectin or fibronectin, thereby cures following disease chronic venous insufficiency, the tip oedema, anti-lipid, chronic venous disease, varix, varix symptom, venous stasis, eliminate the phlegm, the peripheral vessel disorder, the brain organ is twitched, the cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling, alleviate the skelagia sign, itch alleviates leg swelling, sign eases the pain, thrombosis is prevented and treated stomach ulcer and antispastic, stops the growth of cancer metastasis and anticancer.Concrete grammar is the above-mentioned disease of this compound treatment with doses.Compound at the lining indication is the Xanifolia Y0 that this patent provides, Y1, Y2, Y, Y7, Y8, Y9, Y10, Xanifolia (x), escin, Aescin or its esters, ester class and meta-bolites, or from having structural formula (1A), (1B), (1C) and compound (1D).These compounds contain the female ring of triterpene, two angeloyl groups and sugar chain.These compounds can be from the compd A to X and A1 in X1, select, also can to Z7, select from compound Z1.
This patent provides the application of preparation medicine to reduce the method for Fibronectin or its acceptor, it is characterized in that described Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.This patent also provides transfer and the growth that stops cancer cells, or the method for angiogenesis inhibitor, said here cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
This patent provides the application of preparation medicine to reduce the method for Fibronectin or its acceptor interaction, it is characterized in that described Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Be the secretion that reduces fibronectin specifically.The transfer that stops cancer cells also is provided, or resisting mammal method for cancer, it is characterized in that described method is with effective dose of medicine thing treatment cancer, here said medicine contains the compound compositions that this patent provides, and said cancer comprises mammary cancer, the white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, the nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc., said compound comprise compounds X anifolia Y0, Y1, Y2, Y, Y7, Y8, Y9, Y10, its esters, the ester class, meta-bolites or derivative, they can propose from natural resource, or synthetic.
Experimental result is asked for an interview present patent application and international patent application book (No.PCT/US04/43465, on December 23rd, 2004 submitted, PCT/US05/31900, on September 7th, 2006, PCT/US04/33359, submitted in 200410 months 8 days, PCT/US2007/077273, on August 30th, 2007 submitted), U.S. Patent application book (U.S.Serial No.10/906,303, on February 14th, 2005 submitted, U.S. sequence number No.11/131551, on May 17th, 2005 submitted) thereby, the content of the application for patent that these are being authorized thereby should include in the present patent application all sidedly.
The salt of these compounds comprises sylvite, sodium salt and calcium salt.These salts can suppress chronic venous insufficiency, and the tip oedema is anti-lipid, chronic venous disease, varix, the varix symptom, venous stasis eliminates the phlegm, the peripheral vessel disorder, the brain organ is twitched, cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling, alleviate the skelagia sign, itch alleviates leg swelling, the sign that eases the pain, thrombosis is prevented and treated stomach ulcer and antispastic.
The invention provides the application of preparation medicine, regulate adhesion protein or acceptor, lower cancer cells adhesion ability, said here regulating effect is just comprising the adjusting of (positive), also comprises the regulating effect of negative (negative).Described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Be the secretion that reduces fibronectin specifically.Also provide and stoped the transfer of cancer cells or the method for growth, it is characterized in that described method is with effective dose of medicine thing treatment cancer, here said medicine contains the compound compositions that this patent provides, said cancer comprises mammary cancer, the white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, the nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc., said compound comprises compounds X anifolia Y0, Y1, Y2, Y, Y7, Y8, Y9, Y10, its esters, ester class, meta-bolites or derivative, they can propose from natural resource, or synthetic.Above-mentioned indication compound is described below:
(Z1): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group; 22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
Figure GSB00000006033200151
(Z2): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group; 22-O-(angeloyl groups-2-first butyryl radicals)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
Figure GSB00000006033200161
(Z3): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(2-first propionyl); 22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
Figure GSB00000006033200162
(Z4): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group, 22-O-benzoyl-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
(Z5): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group, 22-O-angeloyl groups-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
Figure GSB00000006033200164
(Z6): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(2-first propionyl)-O-phenmethyl; 22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
Figure GSB00000006033200171
(Z7): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(2-first propionyl)-O-angeloyl groups; 22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
Figure GSB00000006033200172
(Z8): 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-and α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-phenmethyl, 22-O-phenmethyl-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
The invention provides expression, the secretion or synthetic of regulating Fibronectin, or and the interactional compound of Fibronectin the preparation medicine application, described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Be the secretion that reduces fibronectin specifically.Here said compound has structural formula (1B), its esters, ester class, meta-bolites or derivative.
Figure GSB00000006033200174
Wherein R1 is H, hydroxyl, and angeloyl groups, along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group, unsaturated acyl group, the saturated acyl group that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.Wherein R2 is H, angeloyl groups, and ethanoyl, along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group, unsaturated acyl group, the acyl group that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.R4 is CH 2OR6 or COOR6, wherein R6 is a hydroxyl, angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl, saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.R3 is hydrogen or hydroxyl.At R1, among R2 and the R6, have at least one to contain following group: angeloyl groups here; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl; saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound; heterocyclic aromatic compounds, or derivatives thereof.R5 is hydrogen or sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: D-glucose, D-semi-lactosi, L-rhamnosyl, L-arabinose, D-wood sugar, or uronic acid, D-glucuronic acid, D-galacturonic acid, or derivatives thereof, or their combination.
Under certain conditions, the sugar chain that contains of R1 by two in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group; unsaturated acyl group, the acyl group that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.In another case, the sugar chain that contains of R1 by one in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, the sugar chain that R2 contains by one in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.Under a kind of embodiment situation of the present invention, sugar chain that R2 contains or side chain by two in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group; unsaturated acyl group, the acyl group that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, R4 is CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain contains of following group at least: angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl; saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound; heterocyclic aromatic compounds, or derivatives thereof.Under a kind of embodiment situation of the present invention, R4 is CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain contains two of following group at least: angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl; saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound; heterocyclic aromatic compounds, or derivatives thereof.Under a kind of embodiment situation of the present invention, R4 is CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain contains two of following group at least: angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group.Under a kind of embodiment situation of the present invention, R4 contains CH 2OR6 or COOR6, the R1 in the structural formula is among R2 and the R6; have at least two to contain following group: angeloyl groups, ethanoyl is along root of Dahurian angelica acyl group; the squaw weed acyl group, alkyl, two benzoyls; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.Under a kind of embodiment situation of the present invention, R4 contains CH 2OR6 or COOR6, the R1 in the structural formula among R2 and the R6, has at least two to contain following group: angeloyl groups, benzoyl, saturated acyl group, unsaturated acyl group, or derivatives thereof.Under a kind of embodiment situation of the present invention, R4 is the side chain that contains following group: CH 2OCOCH 3, CH 2The COO-alkyl, CH 2OH, COOH, angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl, saturated acyl group, unsaturated acyl group, the acyl group that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, R5 is a sugar chain, and sugar chain contains one or more following sugar and uronic acid (being not limited to) at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.Under another situation, R5 contains sugar chain or is equivalent to the group of sugar chain effect.Embody under the situation of the present invention at another, R5 is a hydrogen.
Under a kind of embodiment situation of the present invention, R4 is a hydrogen, hydroxyl or CH 3
Under a kind of embodiment situation of the present invention, the C23 of these compounds, C24, C25, C26, CH is contained in C29 and C30 position 3, CH 2OH, CHO, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic compounds, CH 2The O-aromatic base, CH 2The O-heterogeneous ring compound, CH 2The O-heterocyclic aromatic compounds, alkyl, ethanoyl, or derivatives thereof, particularly CH3.
In one case, R1 and R2 contain angeloyl groups separately.
Under another situation, R1 is a sugar chain or side chain, it is characterized in that described sugar chain or side chain contain two angeloyl groups.
Under a kind of embodiment situation of the present invention, R1 and R2 contain benzoyl separately.
Under a kind of embodiment situation of the present invention, R1 is a sugar chain, it is characterized in that described sugar chain is replaced by two benzoyls.
Under a kind of embodiment situation of the present invention, R3 is hydrogen or hydroxyl.
Under a kind of embodiment situation of the present invention, R8 is a hydrogen.
The chemical group of above-claimed cpd is replaced by other chemical group, remove, or to have increased one or several chemical group again is a technology contents of present patent application.And the chemical group of one or several in the compound in present patent application is replaced by other several chemical groups, removes, or has increased one or several chemical group again and can fundamentally not influence the bioactive of them.
The composition that this patent provides, it is characterized in that described composition contains above-claimed cpd, its esters, the ester class, meta-bolites or derivative, the said composition useful as drug is regulated adhesion and albumen, or and Fibronectin interact, described here Fibronectin comprises fibronectin, the protein of integrin family, myosin, vitronectin, collagen protein, ln, the glycosylation cell surface protein, saccharan albumen (polyglycans), the calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen.Specifically, the reduction fibronectin excretory method that this patent provides, but thereby anticancer growth and anticancer disease, cancer described here comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
The medicine that this patent provides, method and composition can be regulated blood vessel and give birth to, the anticancer growth, it is characterized in that described composition contains above-claimed cpd, its esters, the ester class, meta-bolites or derivative, said here cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells, but the adjusting angiogenin 2 (angiopoietin 2) that it is characterized in that the above-mentioned composition forward, the adjusting angiogenin 1 of negative sense (angiopoietin 1) are expressed, secretion or synthetic.
The invention provides expression, the secretion or synthetic of regulating Fibronectin, or and the interactional compound of Fibronectin the preparation medicine application, described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Be the secretion that reduces fibronectin specifically.Here said compound has structural formula (1D), its esters, ester class, meta-bolites or derivative.Specifically, the reduction fibronectin excretory method that this patent provides,
Figure GSB00000006033200201
Wherein R1 is H, angeloyl groups, and ethanoyl, along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl, benzoyl, alkyloyl, unsaturated acyl group, the acyl group that the phenmethyl alkyl replaces, aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.R2 is H, angeloyl groups, and ethanoyl, along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl, benzoyl, saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.R4 is CH 2OR6 or COOR6, wherein R6 is a hydrogen, angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, two benzoyls, benzoyl, saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.R3 is hydrogen or hydroxyl.R5 contains sugar chain, D-glucose or D-semi-lactosi.R7 is COOH.Here at least one is an acyl group among R1 and the R2.
Under of the present invention kind of situation of a kind of embodiment, R7 is CH 3, CH 2OH, in COOH and the COO-alkyl one.Under a kind of embodiment situation of the present invention, R7 is in the following group: CH 3, CH 2OH, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic compounds, CH 2The O-aromatic base, CH 2The O-heterogeneous ring compound, CH 2O-heterocyclic aromatic compounds, alkyl, ethanoyl and its derivative.
Under a kind of embodiment situation of the present invention, the sugar chain that R1 contains by two in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound; heterocyclic aromatic compounds, or derivatives thereof.Under a kind of embodiment situation of the present invention, the sugar chain that R1 contains by one in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound; heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, the sugar chain that R2 contains by one in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl, saturated acyl group; unsaturated acyl group, the saturated acyl group that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.In another case, the sugar chain that contains of R2 or side chain by two in the following group substitute: angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl;, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, R4 is CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain is at least by a replacement in the following group: angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.In another case, R4 is CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain at least by two of following group replace: angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, R4 is CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain at least by two of following group replace: angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group.Embody under the situation of the present invention at another, R4 contains CH 2OR6 or COOR6, wherein R6 is a sugar chain, this sugar chain at least by two of following group replace: angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, benzoyl, saturated acyl group; unsaturated acyl group, the saturated acyl group that the phenmethyl alkyl replaces, aromatic base; acyl group; heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.Another embodies under the situation of the present invention, and R4 contains CH 2OR6 or COOR6, the R1 in the structural formula among R2 and the R6, has at least two to contain following group: angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, squaw weed acyl group, benzoyl, saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, or derivatives thereof.Another embodies under the situation of the present invention, and R4 is the side chain that contains following group: CH 2OCOCH 3, CH 2The COO-alkyl, CH 2OH, COOH, angeloyl groups, ethanoyl, along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl, benzoyl, saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or derivatives thereof.
Under a kind of embodiment situation of the present invention, R5 is a sugar chain, and sugar chain contains one or more following sugar and uronic acid (being not limited to) at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.Under a kind of embodiment situation of the present invention, R5 contains the group that is equivalent to the sugar chain effect.Embody under the situation of the present invention at another, R5 is a hydrogen.
Under a kind of embodiment situation of the present invention, R4 is a hydrogen, hydroxyl or CH 3
Under a kind of embodiment situation of the present invention, 24 in the carbon of these compounds is CH 3Or CH 2OH.Embody under the situation of the present invention at another, the C23 of these compounds, C24, C25, C26, C29 and C30 position are contained CH separately 3, CH 2OH, CHO, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic compounds, CH 2The O-aromatic base, CH 2The O-heterogeneous ring compound, CH 2The O-heterocyclic aromatic compounds, alkyl, ethanoyl, or derivatives thereof, particularly CH3.
Under a kind of embodiment situation of the present invention, R5 contains sugar chain, and this sugar chain contains L-glucose, D-semi-lactosi, L-sandlwood Tang, or and L-arabinose.
Under a kind of embodiment situation of the present invention, R1 and R2 contain angeloyl groups separately.Under another situation, R1 is a sugar chain or rhamnosyl, it is characterized in that described sugar chain or rhamnosyl contain two angeloyl groups.
Under a kind of embodiment situation of the present invention, R3 is H or OH.
These compounds can propose or synthetic from natural resources.
The chemical group of above-claimed cpd is replaced by other chemical group, remove, or to have increased one or several chemical group again is a technology contents of present patent application.And the chemical group of one or several in the compound in present patent application is replaced by other several chemical groups, removes, or has increased one or several chemical group again and can fundamentally not influence the bioactive of them.
This patent provides the method for preparing the following disease of heal with drugs.It is characterized in that described disease is a chronic venous insufficiency, the tip oedema, anti-lipid, chronic venous disease, varix, the varix symptom, venous stasis eliminates the phlegm, the peripheral vessel disorder, the brain organ is twitched, cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling alleviates the skelagia sign, and itch alleviates leg swelling, the sign that eases the pain, thrombosis is prevented and treated stomach ulcer and antispastic, stops the growth of cancer metastasis and anticancer.Concrete grammar is the above-mentioned disease of compositions-treated with doses, and said composition contains above-claimed cpd or contains a kind of compound, and this compound contains these compounds and contains the female ring of triterpene; two angeloyl groups are (or along root of Dahurian angelica acyl group, squaw weed acyl group; angeloyl groups preferably) and sugar chain, sugar chain contains glucose, semi-lactosi; rhamnosyl, pectinose, wood sugar; Fucose, Ah coughing up's sugar, altrose; gulose, idose, lyxose; seminose, ribose, sorbose; tagatose, talose, fructose; or uronic acid, glucuronic acid, galacturonic acid; or derivatives thereof; or their combination (glucose preferably, semi-lactosi, pectinose; glucuronic acid, galacturonic acid).
This patent provide expression that the application of preparation medicine regulates Fibronectin, secretion, synthetic or and the interactional method of Fibronectin, it is characterized in that described Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Be the secretion that reduces fibronectin specifically.
This patent also provides the application of preparation medicine to be suppressed at cell transfer and growth, it is characterized in that described method is to realize that by the characteristic that changes cytolemma the characteristic that changes cytolemma here is meant the minimizing Fibronectin.Described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Be the secretion that reduces fibronectin specifically.Concrete grammar is the triterpenoid saponin compound with doses, and this saponin contains two or more angeloyl groups, or with the triterpenoid saponin compound of doses; this compound contains these compounds and contains the female ring of triterpene, and two angeloyl groups are (or along root of Dahurian angelica acyl group; squaw weed acyl group, preferably angeloyl groups) and sugar chain, sugar chain contains glucose; semi-lactosi, rhamnosyl, pectinose; wood sugar, Fucose, Ah coughing up's sugar; altrose, gulose, idose; lyxose, seminose, ribose; sorbose, tagatose, talose; fructose, or uronic acid, glucuronic acid; galacturonic acid, or derivatives thereof, or their combination (glucose preferably; semi-lactosi; pectinose, glucuronic acid, galacturonic acid).
The composition that this patent provides, it is characterized in that described composition contains above-claimed cpd, its esters, the ester class, meta-bolites or derivative, the said composition useful as drug can reduce adhesion and albumen, and described here Fibronectin comprises fibronectin, the protein of integrin family, myosin, vitronectin, collagen protein, ln, the glycosylation cell surface protein, saccharan albumen (polyglycans), the calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen.Specifically, the reduction fibronectin excretory method that this patent provides, but thereby anticancer growth and anticancer disease, cancer described here comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
The composition that this patent provides, it is characterized in that described composition contains above-claimed cpd, its esters, the ester class, meta-bolites or derivative, the said composition useful as drug can reduce adhesion and albumen, and described here Fibronectin comprises fibronectin, the protein of integrin family, myosin, vitronectin, collagen protein, ln, the glycosylation cell surface protein, saccharan albumen (polyglycans), the calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen.
It is characterized in that described medicine can suppress fibronectin expression, secretion or synthetic, thereby can be used for curing following disease disease: chronic venous insufficiency, tip oedema, anti-lipid, chronic venous disease, varix, the varix symptom, venous stasis eliminates the phlegm, the peripheral vessel disorder, the brain organ is twitched, cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling, alleviate the skelagia sign, itch alleviates leg swelling, and sign eases the pain, thrombosis is prevented and treated stomach ulcer and antispastic.Concrete grammar is to manage above-mentioned disease with the composition smelting of doses.
Above-mentioned indication composition is characterized in that described composition contains the triterpenoid saponin compound, and this triterpenoid saponin compound has a kind of of following chemical structure:
3-O-{[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)]-β-D-glucuronic acid pyranoside butyl ester }-21-O ethanoyl-22-O-party returns acyl group-3 β; 16 α; 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group-21, acyl group-3 β returns, 15 α, 16 α, 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-L-rhamnosyl pyrans acyl group-22-O-ethanoyl-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group-21, acyl group-3 β returns, 15 α, 16 α, 21 β, 22 α, 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group-(1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 16 α return in the two parties of 22-; 21 β; 22 α, 24 β, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28 ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β returns, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-O-.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group, 22-O-(2-first propionyl)-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-party returns acyl group-28-O-2-first butyryl radicals-3 β; 15 α, 16 α, 21 β; 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
The composition that this patent provides, it is characterized in that described composition contains above-claimed cpd, said composition can regulate or reduce adhesion and protein expression, secretion or synthetic, and described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.It is characterized in that described composition can be used for curing chronic venous insufficiency, particularly varix, or stop the leg oedema, suppress the cancer growth.Cancer described here comprises bladder cancer, osteocarcinoma, skin carcinoma and mammary cancer, certainly not only these cancers.
The composition that this patent also provides, said composition can regulate or reduce adhesion and albumen, and described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Thereby said composition can be used for curing chronic venous insufficiency, particularly varix, or stops the leg oedema, suppresses the cancer growth.It is characterized in that described composition contains a kind of in the following compound:
A) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
B) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-L-rhamnosyl pyrans acyl group-22 ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
C) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
D) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-O-.
E) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28 ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
F) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-O-.
G) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
H) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-α-L-rhamnosyl pyrans acyl group-22 ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
I) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 15 α; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
J) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
K) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-α-rhamnosyl pyrans acyl group-28 ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
L) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, the two benzoyls of 22-O-)-3 β, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
M) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-D-pectinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, the two benzoyls of 22-O-)-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
N) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)] β-D-wood sugar furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-α-rhamnosyl pyrans acyl group-22-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
O) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)] β-D-wood sugar furans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 15 α; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
P) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)] β-D-wood sugar furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
Q) 3-O-[beta galactose pyrans acyl group (1 → 2)] β-wood sugar furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-α-rhamnosyl pyrans acyl group-28-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
R) 3-O-[beta galactose pyrans acyl group (1 → 2)] β-wood sugar furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
S) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)] β-D-wood sugar furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, two benzoyl-3 β of 22-O-, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
T) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)] β-D-wood sugar furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-α-L-rhamnosyl pyrans acyl group-22-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
U) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-D-wood sugar furans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
V) 3-O-[beta galactose pyrans acyl group (1 → 2)]-β-D-wood sugar furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-O-.
W) 3-O-[beta galactose pyrans acyl group (1 → 2)] β-D-wood sugar furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-α-rhamnosyl pyrans acyl group-28-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
X) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-D-wood sugar furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β returns, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin in the two parties of 22-O-.
The composition that this patent also provides, said composition can regulate or reduce adhesion and protein expression, secretion or synthetic, and described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Thereby said composition can be used for curing chronic venous insufficiency, particularly varix, or stops the leg oedema, suppresses the cancer growth.It is characterized in that described composition contains a kind of in the following compound:
A1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-angeloyl groups, 22-O-benzoyl-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
B1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)] β-D-glucuronic acid pyrans acyl group-21-O-(3; the two benzoyls of 4-)-and α-L-rhamnosyl pyrans acyl group-22-ethanoyl-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
C1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-angeloyl groups; 22-O-benzoyl-3 β; 15 α; 16 α; 21 β; 22 α, 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
D1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-angeloyl groups; 22-O-benzoyl-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
E1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-(the 3-angeloyl groups of α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-F); the 4-benzoyl)-α-rhamnosyl pyrans acyl group-28-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
F1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-angeloyl groups; 22-O-benzoyl-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
G1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-benzoyl, 22-O-angeloyl groups-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
H1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3-benzoyl; the 4-angeloyl groups)-α-L-rhamnosyl pyrans acyl group-22-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
I1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-benzoyl; 22-O-angeloyl groups-3 β; 15 α; 16 α; 21 β; 22 α, 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
J1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-benzoyl; 22-O-angeloyl groups-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
K1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3-benzoyl; the 4-angeloyl groups)-α-rhamnosyl pyrans acyl group-28-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
L1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-benzoyl; 22-O-angeloyl groups-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
M1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-alpha-D-xylose pyrans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-angeloyl groups, 22-O-benzoyl-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
N1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-alpha-D-xylose pyrans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3-angeloyl groups; the 4-benzoyl)-α-L-rhamnosyl pyrans acyl group-22-O-ethanoyl--3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
O1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-alpha-D-xylose pyrans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21-O-angeloyl groups, 22-O-benzoyl-3 β, 15 α; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
P1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-alpha-D-xylose pyrans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21-O-angeloyl groups; 22-O-benzoyl-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
Q1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-β-wood sugar pyrans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3-angeloyl groups; the 4-benzoyl)-α-rhamnosyl pyrans acyl group-28-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
R1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-β-wood sugar pyrans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-angeloyl groups; 22-O-benzoyl-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
S1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-D-wood sugar pyrans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-benzoyl, 22-O-angeloyl groups-3 β, 15 α; 16 α; 21 β, 22 α, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
T1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-D-wood sugar pyrans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-(3-benzoyl; the 4-angeloyl groups)-α-L-rhamnosyl pyrans acyl group-22-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
U1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-D-wood sugar pyrans acyl group (1 → 3)-D-glucuronic acid pyrans acyl group-21-O-benzoyl, 22-O-angeloyl groups-3 β, 15 α; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin.
V1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-β-D-wood sugar pyrans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-benzoyl; 22-O-angeloyl groups-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
W1) 3-O-[beta galactose pyrans acyl group (1 → 2)]-β-D-wood sugar pyrans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3-benzoyl; the 4-angeloyl groups)-α-rhamnosyl pyrans acyl group-28-ethanoyl-3 β; 16 α; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
X1) 3-O-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-D-wood sugar pyrans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O-benzoyl; 22-O-angeloyl groups-3 β, 16 α, 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin.
The above-mentioned triterpenoid saponin of mentioning at this patent with special construction can be used to cure chronic venous insufficiency, particularly varix, or stops the leg oedema.These triterpenoid saponins with special construction also can be used to stop cancer metastasis simultaneously, suppress the cancer growth.Cancer described here comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.These triterpenoid saponins with special construction also can be used to influence the structure and the adhesion process of cytolemma simultaneously.Specifically, the method for treatment comprises regulates or the minimizing Fibronectin, thereby stops cancer metastasis and growth; Or the tackifying ability of reduction cancer cells.Described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Top indication compound is the triterpenoid saponin compound; this compound contains triterpenoid saponin unit or other sapogenin and in carbon 21 and/or 22, or 28 have one or two angeloyl groups at least (or along root of Dahurian angelica acyl group for the position; squaw weed acyl group, or their combination) directly be connected on the sapogenin or on the sugar chain.These compounds can be used for curing chronic venous insufficiency, particularly varix, or stop the leg oedema, stop cancer metastasis, suppress the cancer growth.This compound has a pentacyclic triterpenoid saponin unit and at least two angeloyl groups (or along root of Dahurian angelica acyl group, squaw weed acyl group, or their combination) and sugar chain specifically.Angeloyl groups (or along root of Dahurian angelica acyl group, squaw weed acyl group, or their combination) is connected on the side chain of an end of sapogenin, and sugar chain is connected on the side chain of the other end.Angeloyl groups can be replaced by the individual group that is equivalent to angeloyl groups of function.Sugar chain is connected in 3 in carbon or other position, contains one or more following sugar: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination (D-glucose preferably, D-semi-lactosi, L-can draw uncle's sugar, D-glucuronic acid, D-galacturonic acid, or their combination).CH 3, CH 2OH, COOH or ethanoyl also may be connected in 23 to 30 in carbon separately.The antitumour activity of these compounds depends on its chemical structure, promptly contains the such function group of picture angeloyl groups (or along root of Dahurian angelica acyl group, squaw weed acyl group, or their combination).
This patent also provides the compound compositions that contains following chemical structure: (a), and (b), (c), (d)
Wherein R1 and R2 contain angeloyl groups, along root of Dahurian angelica acyl group, and squaw weed acyl group, ethanoyl, or their combination (preferably angeloyl groups).Under a kind of embodiment situation of the present invention, R1 and R2 contain angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group; heterogeneous ring compound; heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.
Wherein R1 and R2 contain angeloyl groups, along root of Dahurian angelica acyl group, and squaw weed acyl group, ethanoyl, or their combination (preferably angeloyl groups).Under a kind of embodiment situation of the present invention, R1 and R2 contain angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group; heterogeneous ring compound; heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.Under a kind of embodiment situation of the present invention, this compound contains sugar chain.This sugar chain contains glucose, semi-lactosi, pectinose, or their composition.Embody under the situation of the present invention at another kind, this sugar chain contains in the following sugar at least: this sugar chain contains glucose, semi-lactosi, pectinose, rhamnosyl, wood sugar, uronic acid, glucuronic acid, galacturonic acid, or their composition.
Figure GSB00000006033200292
R1 wherein, R2 or R3 contain angeloyl groups, along root of Dahurian angelica acyl group, squaw weed acyl group, ethanoyl, or their combination (be preferably in R1, having two among R2 or the R3 is angeloyl groups).In one case, at R1, have two among R2 or the R3 at least and contain angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group, heterogeneous ring compound, heterocyclic aromatic compounds; or contain the acid of 2-5 carbon, or derivatives thereof.Under a kind of embodiment situation of the present invention,, have one among R2 or the R3 at least and contain sugar chain at R1.This sugar chain contains angeloyl groups, ethanoyl, and along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group, heterogeneous ring compound, heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.
Containing under the situation of sugar chain, this sugar chain is connected and R1, the end (d) that R2 is relative with R3. and this sugar chain contains glucose, semi-lactosi, pectinose, or their composition.Under a kind of embodiment situation of the present invention, this sugar chain contains in the following sugar at least: glucose, semi-lactosi, pectinose, rhamnosyl, wood sugar, uronic acid, glucuronic acid, galacturonic acid, or their composition.
Under a kind of embodiment situation of the present invention, sugar chain contains one or more following sugar and uronic acid (being not limited to) at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.R1, R2 and R3 can be connected the other end of female ring.
Under a kind of embodiment situation of the present invention, above the indication compound be the triterpenoid saponin compound, this compound contains two angeloyl groups at least, along root of Dahurian angelica acyl group, the squaw weed acyl group, ethanoyl, or their combination preferably contain two angeloyl groups.Under a kind of embodiment situation of the present invention, at least two is angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group; heterogeneous ring compound; heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.
Under a kind of embodiment situation of the present invention, at least one side chain is a sugar chain, and this sugar chain contains two following groups: angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group, heterogeneous ring compound, heterocyclic aromatic compounds; or contain the acid of 2-5 carbon, or derivatives thereof.
Under a kind of embodiment situation of the present invention, above-mentioned indication compound contains sugar chain, and this sugar chain contains glucose, semi-lactosi, pectinose or their composition.Under a kind of embodiment situation of the present invention, this sugar chain contains in the following sugar at least: glucose, semi-lactosi, pectinose, rhamnosyl, wood sugar, uronic acid, glucuronic acid, galacturonic acid, or their composition.Under a kind of embodiment situation of the present invention, sugar chain contains one or more following sugar and uronic acid (being not limited to) at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.
Triterpenoid saponin compound contains the following chemical structure just antitumour activity, and this antitumour activity reaches to stop cancer metastasis and growth by reducing Fibronectin.
Wherein, have two among R2 or the R3 at least and contain angeloyl groups, ethanoyl at R1; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group; heterogeneous ring compound; heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.Under a kind of embodiment situation of the present invention,, have one among R2 or the R3 at least and contain sugar chain at R1; this sugar chain contains angeloyl groups, and ethanoyl is along root of Dahurian angelica acyl group; the squaw weed acyl group, alkyl, benzoyl; saturated acyl group, unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces; aromatic base, acyl group, heterogeneous ring compound; heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.In another case, R1, R2 or R3 contain angeloyl groups, and along root of Dahurian angelica acyl group, squaw weed acyl group, ethanoyl, or their combination are preferably in R1, have at least two to contain angeloyl groups among R2 or the R3.
Under a kind of embodiment situation of the present invention, R5 contains sugar chain, and this sugar chain contains following sugar and uronic acid at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.Under a kind of embodiment situation of the present invention, sugar chain contains one or more following sugar and uronic acid (being not limited to) at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.Under a kind of embodiment situation of the present invention, this sugar chain contains glucose, semi-lactosi, rhamnosyl, pectinose, or derivatives thereof, or their combination.Under a kind of embodiment situation of the present invention, this sugar chain contains uronic acid, semi-lactosi, and pectinose, wherein uronic acid comprises glucuronic acid, galacturonic acid.In another case, this sugar chain contains uronic acid, glucose, and pectinose, wherein uronic acid comprises glucuronic acid, galacturonic acid.
Under a kind of embodiment situation of the present invention, R1, R2 and R3 can be connected on other position of female ring.
Under a kind of embodiment situation of the present invention, above the indication compound be the triterpenoid saponin compound, this compound contains two angeloyl groups at least, along root of Dahurian angelica acyl group, the squaw weed acyl group, ethanoyl, or their combination preferably contain two angeloyl groups.Under a kind of embodiment situation of the present invention, at least two is angeloyl groups, ethanoyl; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; benzoyl, saturated acyl group, unsaturated acyl group; the alkyloyl that the phenmethyl alkyl replaces, aromatic base, acyl group; heterogeneous ring compound; heterocyclic aromatic compounds, or contain the acid of 2-5 carbon, or derivatives thereof.
Under a kind of embodiment situation of the present invention, this compound has at least a side chain to contain sugar chain, and this sugar chain contains angeloyl groups; ethanoyl, along root of Dahurian angelica acyl group, the squaw weed acyl group; alkyl, benzoyl, saturated acyl group; unsaturated acyl group, the alkyloyl that the phenmethyl alkyl replaces, aromatic base; acyl group, heterogeneous ring compound, heterocyclic aromatic compounds; or contain the acid of 2-5 carbon, or derivatives thereof.Under a kind of embodiment situation of the present invention, this compound contains a sugar chain, and this sugar chain contains glucose, semi-lactosi, pectinose, or derivatives thereof, or their combination.Under a kind of embodiment situation of the present invention, this sugar chain contains following sugar and uronic acid at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.Under a kind of embodiment situation of the present invention, sugar chain contains one or more following sugar and uronic acid (being not limited to) at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.
This patent also provides a kind of composition, it is characterized in that described composition contains the above-claimed cpd of effective dose, its esters, the ester class, meta-bolites, or derivative, the said composition useful as drug reduces Fibronectin and expresses, secretes or synthesize, stop the transfer or the growth of cancer cells, the treatment cancer, said here cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.Contain specifically chemical structure (d) or compound (e) or sapogenin have anticancer, or antiviral activity.
Above-mentioned indication can be regulated or reduce Fibronectin and express, secretes or synthesize; stop the transfer or the growth of cancer cells; anticancer or antiviral composition; it is characterized in that described composition contains triterpenoid saponin compound; this saponin contains two side chains at least; this two side chain contains angeloyl groups, and trans (trans) is connected on the adjacent carbon potential, on these two side chain cis (cis) under another situation are connected optionally carbon potential.Under another situation, this two side chain is connected on the acyl group.Under another situation, this two side chain is connected on the unsaturated function group.Be connected on the non-conterminous carbon potential in these two side chain cis (cis) under another situation.Under another situation, this two side chain connects and contains a function group that is equivalent to the angeloyl groups function.
Above-claimed cpd can be used for regulating or to reduce Fibronectin, stops the transfer or the growth of cancer cells, chronic venous insufficiency, tip oedema, anti-lipid, chronic venous disease, varix, varix symptom, venous stasis eliminates the phlegm, the peripheral vessel disorder, and the brain organ is twitched, the cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling alleviates the skelagia sign, itch, the leg swelling that disappears, the sign that eases the pain, thrombosis is prevented and treated stomach ulcer and antispastic.Concrete grammar is the above-mentioned disease of compositions-treated with doses.
This patent provides a kind of growth and antiphlogistic method that stops cancer cells, it is characterized in that described method goes medical cancer and inflammation with the above-claimed cpd of effective dose.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.
This patent also provides a kind of detumescence, treats the method for following disease: chronic venous insufficiency, tip oedema, anti-lipid and chronic venous disease, varix, the varix symptom, venous stasis eliminates the phlegm, the peripheral vessel disorder, the brain organ is twitched, cerebral circulation disorder, cerebral edema, psychosis, dysmenorrhoea, hemorrhoid, postoperative swelling, alleviate the skelagia sign, itch, leg swelling disappears, the sign that eases the pain, thrombosis is prevented and treated stomach ulcer and antispastic.Concrete grammar is the above-mentioned disease of compositions-treated with doses.
This patent also provides a kind of composition that contains above-claimed cpd, it is characterized in that described composition can be used for preparing the pharmacological agent cancer, suppresses virus, brain aging improves memory and brain function, the enuresis, the urgent urination frequent micturition, dementia, presenile dementia, autism, brain injury, Parkinson's disease, or other disease that causes by brain insufficiency, sacroiliitis, rheumatism, it is bad to circulate, arteriosclerosis, Reynolds illness, stenocardia, heart function disorder, coronary heart disease, headache, dizzy, the renal function disorder, cardiovascular disorder suppresses NF-Kappa B activation, cerebral edema, breathe urgent symptom grouping, respiratory virus disease (respiratory viral diseases); Chronic venous insufficiency; Ypotension; Chronic venous disease; Ivy extract; Anti-inflammatory; Anti-hemorrhoid, the tip oedema; Varix; Influenza; Oedema after the wound; Postoperative swelling; Suppress thrombosis, suppress ethanol and absorb; Hypoglycemic; Adjust the level of thyroliberin and Kendall compound, premature ejaculation, impotence and treatment diabetes.
This patent also provides the application of a kind of composition at the preparation medicine, it is characterized in that described composition can be used for anti-multiple sclerosis (AntiMS), anti-anaemia (antianeurysm), Zhichuan, anti-bradykinin, anti-capillary hemorrhage, anti-headache, anti-cervicobrachialgia, anti-eclampsia, Ivy extract, anti-encephalitis, anti-epiglottitis, exudation resistance, anti influenza, anti-fracture, antigingivitis, anti-hemotoncus, herpes, antihistaminic, anti-hydrarthrosis, anti-meningitis, oxidation resistant, periodontitis, anti-phlebitis, anti-pleuritis, anti-trachyphonia, anti-rhinitis, anti-tonsillitis, antiulcer agent, varicosis, anti-vertigo, anticancer, Kendall compound takes place, the enuresis, sterilant, haemolysis, hyaluronidase inhibitor, lymphagogue, short sodium is urinated, agricultural chemicals, the hypophysis stimulant, thymolytic, protect protecting of blood vessel with vein.
Thiazolinyl is the structure of undersaturated wire or branch-like, or the combination of the two, contains 1-7 carbon with a plurality of pairs of keys.The alkynyl compounds example is a lot, as vinyl, and propenyl, pseudoallyl, butenyl, s-butenyl, t-propenyl, pentenyl, hexenyl, butadienyl, pentadienyl and hexadienyl.
Aromatic base is a function group, the organic compound of deriving out from aromatic compound such as benzene, the aromatic ring-shaped system that contains the 1-3 phenyl ring that 6-14 carbon is formed.If plural aromatic nucleus together, adjacent ring will be shared common key and connect together.The example of this compounds such as phenol, how phenol.Aromatic base can be substituted by one or more other groups, as halogen, and alkyl or alkoxyl group.
Acyl group is a function group, gets from the organic acid decarboxylize, and acyl compounds can be write as-COR, wherein is two keys between carbon and the Sauerstoffatom.The title back of acyl compounds with-yl is ending, as formyl radical (formyl), ethanoyl (acetyl), propionyl (propionyl), butyryl radicals (butyryl) and this formyl radical (benzoyl).This formyl radical (benzoyl), C 6H 5COR gets from the phenylformic acid decarboxylize.
Heterogeneous ring compound is to contain the heterocyclic compound; so-called heterocycle is meant non-aromatic ring; promptly contain the heteroatomic independent ring of 1-4 or link to each other with second ring, this second ring is the assorted aliphatics ring of 3-7 carbon and contains 0-4 heteroatoms, aromatic base; or assorted aromatic base; here the assorted aliphatics of indication has tetramethyleneimine acyl group, pyrazinyl, morpholinyl; tetrahydrofuran base, imidazoles acyl group and parathiazan base etc.Assorted aliphatic acyl radical is that heterocyclic arene is sloughed hydrogen and obtained.
Alkyl group (Alkanoyl) is the general name that contains the organic compound of RCO-function group, and wherein R is a hydrogen, or alkyl.Preferred alkyl group has ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl and acyl group.
Alkenyl is alkene hydroxyl (an alkene carbonic acyl radical), as amylene carbonic acyl radical (along root of Dahurian angelica acyl group) and hexene carbonic acyl radical (angeloyl groups).
Alkyl (Alkyl) only contains the group of hydrogen and carbon atom, chain, and branch-like, ring-type, double-ring, or their combination contain the 1-18 carbon atom.As methyl, ethyl, propyl group, sec.-propyl, butyl, s-and t-butyl, amyl group, hexyl, heptyl, octyl group, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, cyclopropane base, tetramethylene base, pentamethylene base and cyclohexyl etc.
The benzoyl alkyl substitutes alkyl group and is meant a straight chain or a ramose 1-6 alkyl chain length by at least one benzoyl and the group that alkyl replaces, and wherein phenmethyl is to be connected on the carbon 1-6 position of straight chain or ramose alkyl group.The phenacyl isobutyryl is the first-selection that this patent benzoyl alkyl substitutes alkyl group.
Sugar chain is a molecule fragment of saponin, contains to suppress a plurality of sugar or uronic acid.
Isobutyryl is the different name of 2-methylpropionyl.
Y and Y3 are same compounds.
YM and (ACH-Y) be same compound.
This patent provides a kind of medicine that changes the cancer cell membrane characteristic, it is characterized in that described medicine can stop the transfer and the growth of cancer cells, or angiogenesis inhibitor.Described here cancer cell membrane characteristic comprises Fibronectin.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.Described here method is with compounds X anifolia Y0, Y1, and Y2, Y, Y7, Y8, Y9, Y10, its esters, the ester class, or meta-bolites is handled above-mentioned cancer cells.
The method and composition that this patent provides a kind of anticancer to grow and shift is characterized in that described method and composition can anticancer growth and transfer by changing the cancer cell membrane characteristic.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.Described here method is with compounds X anifolia Y0, Y1, and Y2, Y, Y7, Y8, Y9, Y10, its esters, the ester class, or meta-bolites is handled above-mentioned cancer cells.Compound also comprises other compound that this patent provides.
This patent proof compounds X anifolia-Y is that a kind of DNA suppresses medicine or microtubule drug target (DNA-inhibition or microtubule-targeting) substitutes or supplementing preparation.The drug combination of use or different with other usefulness (blocking-up M-phase carries out or DNA synthesizes) all will be received good effect separately.Share the composite effect (see U.S. Patent application U.S.Serial Nos.11/683198 for details, on May 7th, 2007 submitted) of receiving inhibition ES2 growth of cancer cells as this patent proof Xanifolia-Y and paclitaxel.
Show that in experimentation on animals compounds X anifolia-Y can prolong the life (seeing the experiment 7,8,9 of the U.S. Patent application U.S.Serial Nos.11/683198 that submitted on May 7th, 2007 for details) of the mouse that suffers from cancer.If compounds X anifolia-Y postpones use, the morning that laboratory animal will be dead (comparing) with the 1st, 4 or 10 day use Xanifolia-Y after the trouble cancer.Experimental result shows the transfer of the cancer cells that Xanifolia-Y can suppress to inoculate.CAM is a lot of for the ovarian cancer cell adhesion molecule, and Fibronectin is present among cancer cells and the mesothelial cell.Because the result that Xanifolia-Y regulates, albumen has lost the possibility that tackiness has just stoped contactin.Xanifolia-Y and cytolemma interaction has specifically just changed adhesion and the proteic position of sticking together.
Experimental result also shows Xanifolia-Y to the toxic effect of cancer cells, and it can kill ovarian cancer cell.But the growth of Xanifolia-Y anticancer prolongs the life of suffering from the cancer mouse.And medication more early, and the time that the life of trouble cancer mouse prolongs is of a specified duration more.Xanifolia-Y can also stop or the transfer of anticancer.Postpone and use Xanifolia-Y for trouble cancer mouse, make cancer cells have an opportunity to transfer to leather lining face between after birth (mesothelium lining), cause more growth of cancer cells and quicken dead mouse.Adhesion molecule plays an important role in cancer metastasis.Our experimental result shows, can suppress cytoadherence on the wall of triangular flask according to compounds X anifolia-Y, and the compound of Xanifolia-Y family can suppress the secretion of Fibronectin.That is to say that Xanifolia-Y can stop the function of adhesion molecule, regulate Fibronectin, cover Fibronectin.In other words, Xanifolia-Y has changed the structure of cytolemma indirectly, thereby has changed proteic structure, or the position, makes it lose the adhesion performance.Described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Fibronectin particularly.
Fibronectin (Fibronectin) is a kind of glycoprotein, and it is combined in film on (membranespanning receptor) albumen of acceptor, includes to integrate element, collagen protein, scleroproein and heparin sulfate albumen.The growth of fibronectin and tumour is shifted relevant.The method and composition that this patent provides can be regulated the genetic expression of fibronectin, stops the secretion of fibronectin, reduces the acceptor of fibronectin, reduces the adhesion ability of fibronectin, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
A kind of glycoprotein seen of vitronectin (Vitronectin) in blood plasma and extracellular matrix more.Vitronectin is relevant with cancer metastasis and malignancy of tumorization.The method and composition that this patent provides can be regulated the genetic expression of vitronectin, stops the secretion of vitronectin, reduces the acceptor of vitronectin, reduces the adhesion ability of vitronectin, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
Integrating plain (Integrins) is the acceptor of cell surface, and they and extracellular matrix interact, and determine the shape of cell, locomotivity and the cycle of regulating cell.Integrate and plainly to work during to other cell and tissue adhesion at cell.The integration element is gone back in the signal conductive process and is worked.The method and composition that this patent provides can be regulated and integrate plain genetic expression, stops and integrates plain secretion, reduces the plain adhesion ability of integrating, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
Laminin (Laminins) class glycoprotein, the constituent material of the structure firmware of the basement membrane of nearly all animal tissues (basement membranes).Laminin is hidden and is combined in the extracellular matrix that is associated with cell.The genetic expression that suppresses laminin will reduce the adhesion ability of cancer cells, and anticancer shifts or growth.But the sticking plain genetic expression of the method and composition regulating course that this patent provides stops the secretion of laminin, reduces the adhesion ability of laminin, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
Cell adhesion molecule CAM (CAM cell adhesion molecules) is at a kind of albumen of cell surface, it with other cell bonded process in work.The genetic expression that suppresses confluent monolayer cells adhesion molecule CAM will reduce the adhesion ability of cancer cells, and anticancer shifts or growth.The genetic expression of the method and composition that this patent provides is adjustable ganglion cell's adhesion molecule CAM stops the secretion of cell adhesion molecule CAM, reduces the adhesion ability of cell adhesion molecule CAM, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
Collagen protein (Collagen) is the major protein in the animal conjunctive tissue.The genetic expression that suppresses collagen protein will reduce the adhesion ability of cancer cells, and anticancer shifts.The method and composition that this patent provides can be regulated the genetic expression of collagen protein, stops the secretion of collagen protein, reduces the adhesion ability of collagen protein, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
Tough sticking element-C (Tn-C Tenascin-C) be a kind of extracellular protein it help the growth of cancer cells, the invasion and vasculogenesis.The method and composition that this patent provides can suppress the secretion of tough sticking element, and anticancer shifts or growth.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.
Vasculogenesis (Angiogenesis) is the process of cardiovascular generation.It is a kind of normal g and D process, also can become tumour changes into the state that cancerates from dormant state important step.Angiogenin (Angiopoietins) is a proteinoid somatomedin, can regulate vasculogenesis.(ANG) (ANGPT) comprising angiogenin 1 (angiopoietin 1) (ANGPT1) for the angiogenin of having determined (angiopoietin), angiogenin 2 (angiopoietin 2) (ANGPT2), angiogenin 3 (angiopoietin 3) (ANGPT3), angiogenin 4 (angiopoietin 4) (ANGPT4), angiogenin 5 (angiopoietin 5) (ANGPT5), angiogenin 6 (angiopoietin 6) (ANGPT6) and angiogenin 7 (angiopoietin 7) (ANGPT7).(angiopoietin-like 1 also to comprise angiogenin-class 1, angiogenin-class 2 (angiopoietin-like 2) (ANGPTL2), angiogenin-class 3 (angiopoietin-like 3) (ANGPTL3), angiogenin-class 4 (angiopoietin-like 4) (ANGPTL4), angiogenin-class 5 (angiopoietin-like 5) (ANGPTL5), angiogenin-class 6 (angiopoietin-like 6) (ANGPTL6) and angiogenin-class 7 (angiopoietin-like 7) (ANGPTL7), here angiogenin 1 (angiopoietin 1) (ANGPT1) is positive adjusting angiogenesis factor, can promote vasculogenesis, angiogenin 2 (angiopoietin 2) is the adjusting angiogenesis factor of bearing (ANGPT2) and angiogenin 1 (angiopoietin 1) antagonism.The medicine that this patent provides, method and composition can be regulated expression, the secretion or synthetic of angiogenin, anticancer growth.Described here cancer cell membrane characteristic comprises Fibronectin.Here said cancer comprises mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma etc.Concrete grammar is that the above-mentioned composition that this patent with effective dose provides is handled cancer cells.But the adjusting angiogenin 2 of the composition forward that this patent provides (angiopoietin 2), the adjusting angiogenin 1 of negative sense (angiopoietin 1).
Described here method is with compounds X anifolia Y0, Y1, and Y2, Y, Y7, Y8, Y9, Y10, its esters, the ester class, or meta-bolites is handled above-mentioned cancer cells.
The microarray experimental result shows that compound Y and YM (ACH-Y) can regulate the genetic expression of angiogenin (angiopoietin) family among the cancer cells ES2, promote angiogenin 2 (angiopoietin2) (ANGPT2), and suppress angiogenin 1 (angiopoietin 1) (ANGPT1).
This patent provides angiogenesis inhibitor, thereby can be suppressed at the compound of cell transfer and growth, and this compound comprises compounds X anifolia Y0, Y1, Y2, Y, Y7, Y8, Y9, Y10, ACH-Y, and salt, class ester class or meta-bolites, and have chemical structure (1A), and (1B), compound (1C) and (1D).Here detailed directions is with compounds X anifolia Y0, Y1, and Y2, Y, Y7, Y8, Y9, Y10, its esters, the ester class, or meta-bolites is handled above-mentioned cancer cells.
Under a kind of embodiment situation of the present invention, these compounds contain the female ring of triterpene, two angeloyl groups and sugar chain, and they are compd As of providing of this patent to X and A1 to X1, or compound Z1 is to Z7.
Our microarray experimental data shows that compounds X anifolia Y can regulate following expression of gene (representing with the gene code name): ABL2, ADAMTS1, AKR1C3, AMIGO2, ANGPT2, ANKRD11, AP2B1, APEH, APLP2, ARL10C, ARMC4, ARMCX1, ARMCX6, ARNTL2, ARNTL2, ATF3, ATP6V0E, ATP6V1B2, ATP6V1C1, ATP6V1C1, BCL2A1, BCL6, BRI3, BTD, C14orf109, C14orf78, C17orf32, C6orf65, C9orf10, C9orf103, CAD, CAV1, CAV2, CBLL1, CCL20, CD33L3, CEBPB, CEP4, CFH/ //CFHL1, CHRDL1, CITED2, CITED2, CLDN14, CLN8, CLTA, CNAP1, COG6, COL18A1, COL4A2, COL5A1, COL5A2, COL6A3, COPG, CPM, CPNE3, CPSF1, CSRP2BP, CSTB, CTNS, CXCL2, DDB1, DDIT3, DDX20, DKFZP564I1171, DKFZP586J0619, DUSP10, DUSP10, DYRK3, EEF2K, EFEMP1, EMP1, EVC, EVI2A, EXT2, FAM62A, FER1L3, FLJ14466, FLNA, FN1, FN1, GANAB, GDF15, GEM, GNPDA1, GPAA1, GPC6, GPNMB, GPNMB, GUSB, H2AFV, H2AFV, HDAC9, HDLBP, HECW2, HMGA2, HMOX1, HSDL2, HSPBAP1, HSPC196, HYOU1, IDS, IGFBP3, IKBKAP, INSIG1, IP04, IRS2, JAG1, KDELR3, KIAA0251, KIAA0586, KIAA1211, KIAA1462, KIAA1706, KIAA1754, KRT18, KRT7, KRTAP4-7, LAMP2, LEPR, LEPREL1, LHFPL2, LIF, LOC286044, LOC339229, LOC90693, LRRC8E, MAFG, MAGED2, MCTP1, MGC16291, MGC19764, MGC5618, MRPS30, MRPS31, MTERFD3, MYH9, NAGA, NAV2, NCSTN, NEK9, NEU1, NFKBIZ, NMT2, NPC2, NSUN5C, NTNG1, NUP188, OACT2, OS9, P4HA1, P8, PALM2-AKAP2, PALM2-AKAP2, PARVA, PBX2, PDE4DIP, PDIA4, PDIA6, PEG10, PHF19, PIK4CA, PLEKHM1, PLOD1, PLOD2, PPP1R15A, PPP1R15A, PRKDC, PRSS23, PRSS23, PSEN2, PSMD1, PTPRF, PTPRJ, RAB32, RAB9A, RG9MTD1, RGS4, RHOQ, RND3, RNF25, RNPEP/ //UBE2V1/ //Kua/ //Kua-UEV, RNU17D, ROBO4, RRAGC, RRS1, SEC31L1, SERPINB2, SERPINB7, SESN2, SGEF, SGSH, SKIV2L, SLC25A21, SLC35A3, SLC3A2, SMARCA1, SNAPC1, SNF1LK, SPOCD1, SPTAN1, SQSTM1, ST3GAL6, STC2, STX3A, TFPI2, TFPI2, TGFBI, TGM2, THRAP1, TLN1, TMEM60, TNFAIP3, TRIB3, TRIO, TSC2, UAP1L1, UBAP2L, UPP1, URB, USP11, USP5, VDR, WDR4, YTHDF2, ZCCHC9, ZDHHC20, ZFHX1B, ZNF185, ZNF278, ZNF690, ZNF697.
The real result of our microarray shows that compounds X anifolia Y and ACH-Y can suppress following expression of gene (representing with the gene code name): FN1, ITGAV, LAMA4, LAMB2, LAMC1, LAMB1, LAMB1, LAMA4, LAMA5, LAMC1, LAMA2, LAMB1, LAMA3, SCAMP1, TICAM2, SCAMP1, TICAM2, SCAMP1, SCAMP1, CAMK2B, DL1, ICAM3, CEECAM1, ICAM5, SCAMP1, CAMK1G, CAMSAP1, MCAM, CAMTA1, CKN1, ALCAM, DCAMKL2, CEACAM3, CAMK2D, CAMK2B, SCAMP5, CAMK4, NCAM1, CAMK2G, MYH9, MYH10, MYO1D, MYO5A, MYLK, MYO6, MYO5A, MYO1C, MYLK, MYO6, MYLC2PL, MYO10, MYO6, TPM3, MYO1C, BECN1, MYO1E, TPM3, M-RIP, MYO1B, MYO10, MYO5A, M-RIP, MYO10, MYL6, MYOHD1, BECN1, TPM4, MYLK, MYH10, MYOHD1, LOC221875, LOC402643, MYO15B, LOC129285, MYH11, MYO1B, MYO1C, MYO9B, CDH13, CTNNAL1, CDH13, CDH12, CTNNB1, CDH5, CTNND1, CDH2, CTNNA1, CDH2, PCDHB16, CTNNA1, CELSR2, PCDHB6, PCDHB7, CTNND2, PCDHGC3, PCDHGB4, PCDHGA8, PCDHGA12, PCDHGC5, PCDHGC4, PCDHGB7, PCDHGB6, PCDHGB5, PCDHGB3, PCDHGB2, PCDHGB1, PCDHGA11, PCDHGA10, PCDHGA9, PCDHGA7, PCDHGA6, PCDHGA5, PCDHGA4, PCDHGA3, PCDHGA2, PCDHGA1, CTNND1, CDH23, PCDHB12, PCDHB10, PCDH18, CDH20, PCDH9, PCDHGA12, PCDHGA11, PCDHGA10, PCDHGA6, PCDHGA5, PCDHGA3, PCDH7, CDH18, CDH6, CCBE1, COL10A1, COL12A1, COL13A1, COL18A1, COL1A1, COL21A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL9A1, MMP9, P4HA1, P4HA2, P4HB, PCOLCE, PCOLCE2, PCOTH, PLOD1, PLOD2, PLOD3, CIB1, ILK, ITGA2, ITGA3, ITGA4, ITGA6, ITGAV, ITGB1, ITGB1BP1, ITGB2, ITGB5, ITGBL1, TNC, EMILIN1, ICAM1, HSPG2, HPSE, HS2ST1, SDC2.
This patent provides the method for regulating Fibronectin, it is characterized in that described method is very important to the transfer and the anticancer growth that stop cancer cells, and this method comprises the adhesion performance that reduces cancer cells.Described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.Fibronectin particularly.
Following is microarray (MICROARRAY) experimental result:
Y/D is the ratio (multiple) through the cellular gene expression of compound Y processing and unprocessed (D).
YM/D is the ratio (multiple) through the cellular gene expression of compound YM (ACH-Y) processing and unprocessed (D).
Table 1: compound Y and YM are to the influence of the expression of the fibronectin among the cancer cells ES2 (fibronectin)
Mark group ID ??Y/D ??YM/D The gene code name The gene title
??212464_s_at ??-2.7 ??-1.1 ??FN1 Fibronectin 1
??216442_x_at ??-2.6 ??-1.1 ??FN1 Fibronectin 1
??211719_x_at ??-2.6 ??-1.2 ??FN1 Fibronectin 1
??210495_x_at ??-2.5 ??-1.1 ??FN1 Fibronectin 1
The microarray experimental result shows that compound Y and YM (ACH-Y) have suppressed the expression of fibronectin.Use genetic marker 212464_s_at respectively, 216442_x_at; 211719x_at and 210495_x_at verify, handle and the ratio of the cellular gene expression of unprocessed (D) is respectively-2.7 through compound Y, and-2.6 ,-2.6 ,-2.5 times, this illustrates that compound Y can suppress the expression of fibronectin.Use genetic marker 212464_s_at respectively, 216442_x_at, 211719_x_at and 210495_x_at verify, compound YM (ACH-Y) also can suppress the expression of fibronectin, the ratio of the cellular gene expression of processing and unprocessed (D) is respectively-1.1 ,-1.1 ,-1.2,-1.1 times, it is good to be not so good as compound effect.
Table 2: compound Y and YM are to the influence of the expression of the integrin family albumen among the cancer cells ES2 (integrins family) (acceptor of vitreum sphaeroprotein)
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
?202351_at ??-1.??8 ??-1.3 ??ITGAV Integrin family albumen, alpha V (acceptor of vitreum sphaeroprotein, alpha polypeptide, antigens c D51)
?236251_at ??-1.??4 ??-1.4 ??ITGAV Integrin family albumen, alpha V (acceptor of vitreum sphaeroprotein, alpha polypeptide, antigens c D51)
The microarray experimental result shows that compound Y and YM (ACH-Y) have suppressed the expression of integrin family albumen (acceptor of vitreum sphaeroprotein).Verify with genetic marker 202351_at and 236251_at respectively, handle and the ratio of the cellular gene expression of unprocessed (D) is respectively-1.8 through compound Y,-1.4 times, the ratio of the cellular gene expression of compound YM (ACH-Y) processing and unprocessed (D) is respectively-1.3 ,-1.4 times.
Table 3: compound Y and YM are to the influence of the expression of the ln among the cancer cells ES2 (laminin)
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
??202202_s_at ??-2.2 ??-2.0 ??LAMA4 Ln alpha 4
??216264_s_at ??-2.0 ??-2.0 ??LAMB2 Ln alpha 5
??200770_s_at ??-1.9 ??-1.1 ??LAMC1 Ln alpha 6
??211651_s_at ??-1.6 ??-1.7 ??LAMB1 Ln alpha 7
??201505_at ??-1.6 ??-2.0 ??LAMB1 Ln beta 1
The microarray experimental result shows that compound Y and YM (ACH-Y) can suppress the expression of ln.Verify with the different genes mark respectively, handle and the ratio of undressed cellular gene expression is respectively-2.2 ,-2.0 ,-1.9 with compound Y,-1.6 ,-1.6 times, handle and the ratio of undressed cellular gene expression is respectively-2.0 ,-2.0 with YM/ACH-Y,-1.1 ,-1.7 ,-2.0 times.
Table 4: compound Y and YM are to the influence of the expression of the cell adhesion molecule CAM among the cancer cells ES2
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
?201952_at ??-1.9 ??-1.4 ??ALCAM The leukocytic adhesion molecule of activated
?201951_at ??-1.9 ??-1.7 ??ALCAM The leukocytic adhesion molecule of activated
?212425_at ??-1.7 ??-1.5 ??SCAMP1 The membranin 1 that secretory belongings are arranged
?240655_at ??-1.6 ??-1.3 ??ALCAM The leukocytic adhesion molecule of activated
?212417_at ??-1.4 ??-1.4 ??SCAMP1 The membranin 1 that secretory belongings are arranged
?239431_at ??-1.3 ??-1.3 ??TICAM2 Toll-like acceptor transmodulator molecule 2
?212416_at ??-1.3 ??-1.1 ??SCAMP1 The membranin 1 that secretory belongings are arranged
?228234_at ??-1.3 ??-1.3 ??TICAM2 Toll-like acceptor transmodulator molecule 2
?206667_s_at ??-1.3 ??-1.5 ??SCAMP1 The membranin 1 that secretory belongings are arranged
The microarray experimental result shows that compound Y can suppress the expression of gene relevant with adhesion molecule with YM (ACH-Y).Verifying with the different genes mark respectively, handle and the ratio of undressed cellular gene expression is respectively-1.3 to-1.9 times with compound Y, is respectively-1.1 to-1.7 times with the ratio of YM/ACH-Y processing and undressed cellular gene expression.
Table 5: compound Y and YM are to the influence of the expression of the collagen protein collagen protein (collagen) among the cancer cells ES2
Figure GSB00000006033200401
Figure GSB00000006033200411
The microarray experimental result shows that compound Y and YM (ACH-Y) can suppress the expression of collagen protein.Verifying with the different genes mark respectively, handle and the ratio of undressed cellular gene expression is respectively-1.3 to-3.0 times with compound Y, is respectively-1.1 to-3.6 times with the ratio of YM/ACH-Y processing and undressed cellular gene expression.
Table 6: compound Y and YM are to the influence of the expression of the integrin family albumen among the cancer cells ES2 (integrins family)
Figure GSB00000006033200412
Figure GSB00000006033200421
The microarray experimental result show compound Y and YM (ACH-Y) but among the anticancer ES2 with the integrin family gene expression related.Verifying with the different genes mark respectively, handle and the ratio of undressed cellular gene expression is respectively-1.5 to-1.9 times with compound Y, is respectively-1.1 to-2.5 times with the ratio of YM/ACH-Y processing and undressed cellular gene expression.
Table 7: compound Y and YM are to the influence of the expression of the myosin among the cancer cells ES2 (Myosin)
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
??211926_s_at ??-2.2 ??-1.2 ??MYH9 Myosin, heavy polypeptide 9, non-flesh
??212372_at ??-1.7 ??-1.4 ??MYH10 Myosin, heavy polypeptide 10, non-flesh
??212338_at ??-1.7 ??-2.1 ??MYO1D Myoglobulin I D
??204527_at ??-1.6 ??-1.2 ??MYO5A Myosin VA (heavy polypeptide 12, heavy polypeptide)
??202555_s_at ??-1.6 ??-1.2 ??MYLK Myosin, the light polypeptide kinases ///myosin, the light polypeptide kinases
??203215_s_at ??-1.6 ??-1.6 ??MYO6 Myosin VI
??225080_at ??-1.5 ??-1.4 ??MYO1C Myoglobulin I C
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
??224823_at ??-1.5 ??-1.4 ??MYLK Myosin, the light polypeptide kinases
The microarray experimental result show compound Y and YM (ACH-Y) but among the anticancer ES2 with myosin family gene expression related.Verifying with the different genes mark respectively, handle and the ratio of undressed cellular gene expression is respectively-1.5 to-2.2 times with compound Y, is respectively-1.2 to-2.1 times with the ratio of YM/ACH-Y processing and undressed cellular gene expression.
Table 8: compound Y and YM are to the influence of the expression of the calcium conglutination element (cadherin) among the cancer cells ES2
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
?244091_at ??-2.0 ??-1.7 ??CDH13 Calcium conglutination element 13, H-calcium conglutination element (heart)
?202468_s_at ??-1.9 ??-1.6 ??CTNNAL1 Catenin (albumen relevant with the calcium conglutination element), alpha-like 1
?204726_at ??-1.8 ??-1.7 ??CDH13 Calcium conglutination element 13, H-calcium conglutination element (heart)
?207149_at ??-1.7 ??-2.2 ??CDH12 Calcium conglutination element 12, type 2 (N-calcium conglutination element 2)
?201533_at ??-1.5 ??1.2 ??CTNNB1 Calcium conglutination element (albumen relevant with the calcium conglutination element), beta 1,88kDa
?204677_at ??-1.5 ??-1.1 ??CDH5 Calcium conglutination element 5, type 2, VE-calcium conglutination element (blood vessel epithelium)
?208407_s_at ??-1.5 ??-1.7 ??CTNND1 Calcium conglutination element (albumen relevant with the calcium conglutination element), delta 1
?203440_at ??-1.4 ??1.0 ??CDH2 Calcium conglutination element 2, type 1, N-calcium conglutination element (neuronic)
?210844_x_at ??-1.4 ??-1.2 ??CTNNA1 Calcium conglutination element (albumen relevant) with the calcium conglutination element,, alpha 1,102kDa
The microarray experimental result show compound Y and YM (ACH-Y) but among the anticancer ES2 with calcium conglutination element family gene expression related.
Table 9: compound Y and YM are to the influence of the expression of the tough sticking element (tenascin) among the cancer cells ES2
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
?201645_at ??-3.2 ??1.0 ??TNC Tough sticking plain C (hexabrachion)
But the microarray experimental result show among the compound Y anticancer ES2 with tough sticking plain family gene expression related.
Table 10: compound Y and YM are to the influence of the expression of the heparin sulfate albumen (heparin) among the cancer cells ES2
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
?201655_s_at ??-2.4 ??-1.3 ??HSPG2 Acetyl sulfate protein-polysaccharide 2 (perlecan)
?219403_s_at ??-1.4 ??-1.3 ??HPSE Acetyl sulfate proteolytic enzyme
?203284_s_at ??-1.3 ??-1.7 ??HS2ST1 Acetyl sulfate albumen 2-O-changes sulphur enzyme 1
But the microarray experimental result shows the genetic expression of the heparin sulfate protein family among the compound Y anticancer ES2.
Table 11: compound Y and YM are to the influence of the expression of the adhesion molecule CD54 among the cancer cells ES2
Mark group ID ??Y/D ??YM/D Gene symbol The gene title
?202638_s_at ??1.6 ??2.3 ??ICAM1 Intercellular adhesion molecule (CD54), the ERC group virus acceptor
But the microarray experimental result shows the genetic expression of the CD54 among the compound Y irritation cancer cell ES2.
Table 12: compound Y and YM are to expression, secretion or the synthetic influence of the angiogenin among the cancer cells ES2 (angiopoietin)
Mark group ID Y/D YM/D genetic character symbol gene title
Number
205572_at 3.5 1.4 ANGPT2 angiogenins 2 (angiopoietin 2)
211148_s_at 2.5 1.4 ANGPT2 angiogenins 2 (angiopoietin 2)
205609_at-1.1-1.2 ANGPT1 angiogenin 1 (angiopoietin 1)
221009_s_at-1.2-1.4 ANGPTL4 angiogenin class 4 (angiopoietin-L 4)
227533_at-1.5-2.3 ANGPTL1 angiogenin class 1 (Angiopoietin-L 1)
The microarray experimental result shows that compound Y and YM (ACH-Y) can regulate the genetic expression of angiogenin (angiopoietin) family among the cancer cells ES2, secretion or synthetic, angiogenin (angiopoietin 2) (ANGPT2) there is positive regulating effect, to angiogenin 1 (angiopoietin 1) ANGPT1, angiogenin class 1 (angiopoietin like 1) (ANGPTL4) (ANGPTL4) has negative regulating effect with angiogenin class 4 (angiopoietinlike 4)
The summary of fibronectin expression, secretion and study on the synthesis:
Reduced with fibronectin secretion behind the compound xanifolia-Y processing cancer cells ES2.
(F1 and F3 experimental result) handled the fibronectin secretion reduces behind the cancer cells ES2 fundamemtal phenomena with compound xanifolia-Y and determined and describe in our experiment.Show with the immunoblotting measurement result, not with the secretion quantity of cancer cells (DMSO control) fibronectin of compound xanifolia-Y processing and the time all increase.But the secretion numbers of poles of the fibronectin of the cancer cells of handling with compound xanifolia-Y is low or equal zero.The fibronectin excretory phenomenon of this anticancer just can observed after 8 hours with Xanifolia-Y.The fibronectin secretion of anticancer is a physiological phenomenon, and secretion quantity is determined according to following standard:
1. fibronectin is from the viable cell excretory.Have only viable cell to account for after the drug treating and just be used to experiment more than 85%.Surviving with mtt assay of cell determined.
2. come the intensity of the immune spectrum band of each cell sample of stdn with the cell quality.The cell quality is determined with mtt assay, and is measured each cell sample cell quality with MTT unit.
(F4 experimental result) measured with mtt assay, (IC50) dosage (10ug/ml Y) that causes death in the Asia, surpass 95% cell with compound Y handle back 18 hours still alive.The immunoblotting result shows, handles back emiocytosis with compound Y and reduces to the fibronectin in the substratum.The scanning Mierocrystalline cellulose shows that in conjunction with Western bands of a spectrum (average 6 couples of blots) handling back 18 hours excretory fibronectins with compound Y reduces 40%.(F5 experimental result) measured with mtt assay, and it still is what live that 85% cell is handled back 24 hours with compound Y.The immunoblotting result shows that the sample fiber after handling with compound Y connects albumen band and reduces.With after standard becomes MTT unit, drawing numerical value is that fibronectin bonded band intensity reduces by 31% according to 6 couples of blots.Illustrate handle back 24 hours with compound Y after, the fibronectin of emiocytosis reduces 31%.The influence of (F7 experimental result) Paclitaxel pair cell excretory fibronectin, not all cancer therapy drug all can reduce the secretion of fibronectin, and we have selected taxol that this problem is described, and taxol is famous ovarian cancer resistance medicament.We use taxol treatment ES2 cancer cells (10to 50ng/ml, the IC of Paclitaxel 50Be 1.5ng/ml), experimental result shows that taxol does not suppress the excretory effect of fibronectin, and the ES2 cancer cells fibronectin secretion reduction 30-40% that handles with compound Y, the experimental result of this and front is consistent.
(F8 experimental result) is except cancer cells ES2, we also use another Proliferation of Human Ovarian Cell (Hey8A) to do same experiment, the result shows and contrasts (DMSO) and compares, be reduced to 31%, 69% fibronectin secretion and be suppressed and connect albumen with the Hey8A cancer cells eccrine fiber that compound Y handles.
Except ovarian cancer, other human cancer cell also studies in this experiment, and experimental result shows, lung cancer, and bladder cancer, liver cancer, the cancer cells of the cancer of the brain and skin carcinoma is after compounds X anifolia-Y handles, and the fibronectin secretion all is suppressed.
After the Xanifolia-Y processing of (F11 experimental result) lung carcinoma cell (H460) with concentration 20ug/ml, (H460) cancer cells eccrine fiber connection albumen reduction amplitude is 20-60%.
After (F12A experimental result) transitional cell bladder carcinoma cell line (HTB-9) was handled with Xanifolia-Y (10ug/ml), HTB-9 cancer cells eccrine fiber connected albumen and reduces amplitude 50%.
After (F15 experimental result) liver cancer cell (HepG2) was handled with Xanifolia-Y (10ug/ml), HepG2 cancer cells eccrine fiber connected albumen and reduces amplitude 42%.
After (F16 experimental result) brain cancer cell (T98G) is handled with Xanifolia-Y (10ug/ml), T98G emiocytosis fibronectin reduces amplitude 27%, after Xanifolia-Y (20ug/ml) processing, T98G emiocytosis fibronectin reduces amplitude 74%.
After (F17 experimental result) skin cancer cell (SK-Mel-5) was handled with Xanifolia-Y (20ug/ml), SK-Mel-5 cancer cells eccrine fiber connected albumen and reduces amplitude 40-57%.
The similar compounds of compound xanifolia-Y and other saponin connect the research of albumen influence to cancer cells ES2 eccrine fiber
We study (F23 experimental result) the usefulness of the secretion inhibitor fibronectin of the triterpenoid saponin compound O54 that proposes from same plant.Result of study shows that secretion does not have restraining effect to compound O54 to ovarian cancer cell ES2 fibronectin, even under the situation of concentration up to 40ug/ml (rather than common effective concentration 10ug/ml).The result shows that the triterpenoid saponin compound that only has special characteristic (structure) just has this restraining effect.
(F21 experimental result) in order to find out this special function group with this specific character, we have studied the xanifolia-Y3. derivative, ACH-Y (Y3 desaccharification) and AKOH-Y (Y3 removes C21, the angeloyl groups of C22 position).Handle ovarian cancer cell ES2 with the Ach-Y of 20ug/ml, and compare, it is 53-75% that the ES2 eccrine fiber connects albumen reduction amplitude, and the amplitude that reduces with the Ach-Y secretion inhibitor fibronectin of 10ug/ml is very little.The function that AKOH does not have the secretion inhibitor fibronectin to reduce, even the function that does not also have the secretion inhibitor fibronectin to reduce under up to the situation of 80ug/ml in concentration.
We have also studied the beta-escin (F13 experimental result), a kind of triterpenoid saponin compound that contains an angeloyl groups (in 21 in carbon).The result shows that the amplitude that the beta-escin suppresses the reduction of ovarian cancer cell ES2 eccrine fiber connection albumen only has 7% (under 10ug/ml concentration) and 48% (under 20ug/ml concentration).And xanifolia-Y suppresses the amplitude of ovarian cancer cell ES2 eccrine fiber connection albumen reduction up to 49% (under 10ug/ml concentration).
We have also studied (F14, F24 experimental result) other similar compound different with xanifolia-Y and suppress ovarian cancer cell ES2 eccrine fiber and be connected proteic effect, the results are shown in following table.
??ES2??cells ??β-ES-10 ??X-10 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-20 ??AKOH-80
Restraining effect % ??19 ??39 ??34 ??41 ??47 ??34 ??48 Do not have
Except AKOH, all compound samples have shown that all inhibition ovarian cancer cell ES2 eccrine fiber connects proteic effect.Under the situation of concentration, there is not restraining effect up to 80ug/ml yet.Can reach a conclusion according to above experimental result; say that generally saponin has the ovarian cancer cell of inhibition ES2 eccrine fiber and connects proteic effect, but do not have the saponin of angeloyl groups such as AKOH-Y (Y3 removes angeloyl groups) not to connect proteic effect with regard to suppressing ovarian cancer cell ES2 eccrine fiber.Illustrating that 21,22 acetylizes of saponin carbon have this compound suppresses ovarian cancer cell ES2 eccrine fiber to connect proteic effect is important.β-ES-10=compound β-ES (in 10ug/ml concentration); X-10=compounds X (in 10ug/ml concentration); Y0-10=compound Y0 (in 10ug/ml concentration); Y1-10=compound Y1 (in 10ug/ml concentration); Y3-10=compound Y3 (in 10ug/ml concentration); Y7-10=compound Y7 (in 10ug/ml concentration); ACH-Y-20=compd A CH-Y (in 20ug/ml concentration); AKOH-80=compd A KOH (in 80ug/ml concentration);
Except ovarian cancer cell, the effect of other human cancer cell's secretion inhibitor fibronectin is also tested, the result is as shown in the table.
(F25,26,31B experimental result) liver cancer cell
??HepG2 ??β-ES-10 ??X-10 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-30
Restraining effect % ??44 ??42 ??40 ??33 ??48 ??10 ??21
(F27,29 experimental results) lung carcinoma cell
??H460 ??β-ES-20 ??X-20 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-20
Restraining effect % Do not have ??37 ??22 ??13 ??19 ??18 ??28
(F28,30 experimental results) transitional cell bladder carcinoma cell line
??HTB-9 ??β-ES-10 ??X-10 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-30
Restraining effect % ??47 ??38 ??32 ??50 ??51 ??60 Do not have
(figure F31,32 experimental results) brain cancer cell
??T98G ??β-ES-20 ??X-20 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-20
Restraining effect % ??66 ??52 ??22 ??40 ??26 ??24 ??30
(F33 experimental result) skin cancer cell
??SK-MEL-5 ??β-ES-20 ??X-20 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-30
Restraining effect % ??17 ??15 ??27 ??10 ??11 Do not have ??21
After (F20 experimental result) determined to handle with compound xanifolia-Y, the secretion of fibronectin and in intracellular content.
The result: this experimental result shows, after handled with compound xanifolia-Y (1), the fibronectin secretion reduced 46% (quantity be contrast 54%).(2) with after the compound xanifolia-Y processing, intracellular fibronectin content reduces by 70% (quantity is contrast 30%).(3) with after the compound xanifolia-Y processing, beta-actin content no change in the ES2 cell.Prove that thus cell expressing, secretion and synthon are connected all combined thing xanifolia-Y of albumen and suppress
Handle the ES2 cell with compound xanifolia-Y, improve (Ang2) content of angiogenin 2 (Angiopoietin2)
Method: ES2 (human body ovarian cancer cell) cultivates in RPMI 1640 substratum, and 4.5 hundred ten thousand cell cultures in the T75 triangular flask 24 hours are standby.
Drug treating: cultured cells is 5,10 and the Xanifolia-Y3[Y3-5 of 15ug/ml (ultimate density) with concentration respectively, Y3-10, Y3-15] or contrast DMSO[D-10] handle.After 24 hours, cell suspension is in the SDS of 1ml buffering sample liquid (cell extract). and sample (80ul/lane) injects the 10%SDS gel, and electrophoresis carried out under voltage 100volt 2 hours.Albumen changes nitrocellulose filter over to by electrophoresis.Nitrocellulose filter ink marks (blot) blocks with 5% fat-free dry milk in PBS.Ink marks is cultivated with first antibody (goat anti-Ang2, SIGMA A0851) and second antibody (donkey anti-goatAP conjugated, Promega V115A).The immunity bands of a spectrum show with BCIP/NBT colour display system (Promega S3771).
The result as shown in Figure 5, in the cell extract of handling with 15ug/ml Xanifolia-Y, see find the immune bands of a spectrum of angiogenin 2 (Angiopoietin-2) (M.W .66K).But in the Xanifolia-Y of low concentration handles with in the control treatment, do not observe
Angiogenin 2 (Angiopoietin-2) is immune bands of a spectrum (ANGPT2).This result shows, the inclusion angiogenin 2 (Angiopoietin-2) of the ES2 cell of handling with 15ug/mlXanifolia-Y (ANGPT2) content has increased.The result that this result is studied by microarray further confirms.Prove cell expressing and the synthetic increase that all is excited thus.
This patent provides the composition and the method for regulating cancer cells genetic expression, it is characterized in that the genetic expression of described adjusting cancer cells comprises that this patent provides the composition and the method for regulating cancer cells genetic expression, it is characterized in that described accent, comprise that regulating Fibronectin (Fibronectin) expresses output and secretion.Described here Fibronectin comprises protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen (polyglycans), calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and the FAK albumen of fibronectin, integrin family.
This patent provides the composition and the method for regulating vasculogenesis, it is characterized in that described key joint comprise to angiogenin 2 (Angiopoietin-2) (ANGPT2) positive adjusting and pipe generated plain 1 (angiopoietin 1) negative adjusting (ANGPT1).Described composition comprises triterpenoid, and it is most important that the carbon 21 of this compound and/or 22 acetylizes have this regulating effect to this compound.Angeloyl groups is contained in acetylize described here group.Ethanoyl, alkanoyl, alkenoyl and alkyloyl.This triterpenoid contains sugar chain in 5 in carbon can strengthen this regulating effect of this compound.
Experiment is described in detail
Proposition about compound, separate and purify, compounds X anifolia Y is to the influence (using mtt assay) of different human body growth of cancer cells, separate the biologically active components of purifying out, determine its chemical structure, detail such as cell experiment and experimentation on animals is at international patent application book (PCT/US05/31900 and PCT/US2007/077273, on August 30th, 2007 submitted) and U.S. Patent application book (U.S.SerialNo.11/289142, U.S.Serial 10/906303, U.S.Serial No.11/131551 and U.S.Serial Nos.11/683198, on March 7th, 2007 submitted, U.S.Serial No.60/890380, on February 16th, 2007 submitted, U.S.Nos.60/947, on July 3rd, 705,2007 submitted) in careless mistake explanation one by one, the content of the application for patent that these are being authorized thereby should include in the present patent application all sidedly.Microarray
Experiment 1 usefulness compound xanifolia-Y handles little gust of analysis of the ES2 gene expression of cells behind the ES2 cell
This patent with little gust analysis and research genetic expression.54676 genes are studied altogether.
Cell cultures and drug treating: ovarian cancer cell ES2 cultivates in the T-25 triangular flask, and every bottle 4.5 hundred ten thousand cell was cultivated 24 hours.Cultured cells is again with containing xanifolia-Y (Y) or not having the new culture medium culturing 24 hours of the DMSO (D) of xanifolia-Y (Y).The results cultured cells is extracted RNA.3 experiments have been carried out.
The extraction of RNA indicates, hybridization and data analysis
Extract RNA with reagent and method that Qiagen RNeasy Kit. provides from cancer cells.The quality and quantity of RNA use respectively Agilent BioAnalyzer and The ND-1000 spectrophotometer.First and second cDNA bands are synthetic in 2 amplification cycles with Affymetrix T7oligo (dT) marker and method from total RNA of 20ng.Be the biotin-labeled-cRNA that obtains increasing, cDNA MegaScript kit (Ambion) reverse transcription.15.0 the cRNA of the sign of μ g is cut into fragment and uses The ND-1000 spectrograph is measured once more.The cRNA fragment of hybridizing reagent Affymetrix spike-in and sign inserts U133 and 2.0
Figure GSB00000006033200493
Oligonucleotide arrays.(Affymetrix, Inc.Santa Clara CA) include 1,300 to the Affymetrix array, and special oligonucleotide characteristic more than 000 has been represented more than 38,500 important human body gene.Strepavidin is used in the hybridization 16 hours under 45 ℃ and revolution 60rpm of this array then, and R-phycoerythrin conjugate washs on AffymetrixFluidicis Station 450 and dyes.The antistreptavidin that single expansion is given with the vitamin H acyl groupization finishes.This array is used can be self-loading
Figure GSB00000006033200494
3000 with the focal argon laser scanner scanning.Scan image is analyzed with Affymetrix GCOS software (version 1.4) and is carried out quality control matrix record.Preferably the data of each genetic expression are calculated with dChip PM-only model based or Plier algorithm.
Data analysing method
Matched pair technique is compared as follows: handle vs contrast (Y vs D), the analysis Bioconductor package of R mathematical statistics of altered medicine vs contrast (YM/ACY-H vs D) and the processing altered medicine of vs (Y vs YM/ACH-Y) CEL file.Analyze the change gene that can obtain between a considerable number of different samples by Limma.
Undressed data GCRMA method (the many array analysis of the robust) stdn of CEL file.Finish in Bioconductor ( Http:// www.bioconductor.org/).To unprocessed single augmentation data stdn, background is corrected and is summarized according to certain mathematical analysis model.The genetic expression value is each mark, each wafer (chip) with Log2-scaleExpress.The null hypothesis check, genetic expression does not have marked difference between a pair of processing.Finish with LIMMA and Bioconductor.Estimate the variation of genetic expression with experience Bayes theorem (empiricalBayes).Done the comparison of high-grade vs inferior grade (High Grade vs.Low Grade).Unprocessed p value is adjusted with the Benjamnin-Hochberg method, with the appearance (FDR) of controlling false ratio.
Unprocessed p value is adjusted with the Benjamnin-Hochberg method, with the appearance (FDR) of controlling false ratio, and obtains adjusted p value.
Result: ask for an interview table 1 to 12.
Xanifolia-Y suppresses the secretion (immunoblotting) of fibronectin
Experiment 2 (F1)
Method: ovarian cancer cell ES2 cultivates in the T-25 triangular flask of RPMI RPMI-1640 is arranged, and cultivates an evening.At 0 hour, the nutrient solution of cultured cells is changed the new substratum RPMI cultivation that contains xanifolia-Y (Y) (ultimate density 10ug/ml) or do not have the DMSO (D) of xanifolia-Y (Y).The 1st, 2, got the content that the part nutrient solution is measured fibronectin in 4,8 and 24 hours.The content of fibronectin is standard test with immunoblotting with the monoclonal antibody (SIGMA) that the human fiber is connected the special usefulness of albumen.
Result's (also seeing Fig. 1):
1. the emiocytosis fibronectin of handling with DMSO (contrast) is in substratum, amount and the time all increase.The fibronectin of the emiocytosis of handling with Xanifolia-Y is few or do not have.
2. in contrast, fibronectin immunity bands of a spectrum do not observe in the RPMI substratum, and the RPMI substratum contains fetal bovine serum, or normal mouse serum (NS1).
Experiment 3 (F3)
Method: ovarian cancer cell ES2 cultivates in the T-25 triangular flask of RPMI RPMI-1640 is arranged, and cultivates an evening.At 0 hour, the nutrient solution of culturing cell is changed the new substratum RPMI that contains xanifolia-Y (Y) (ultimate density 10ug/ml) or DMSO (D) cultivate.Wherein be divided into A group and B group again, changed the new nutrient solution of no medicine respectively at the 4th and 8 hour.2,4, got the content that the part nutrient solution is measured fibronectin in 8 and 24 hours.The content of fibronectin is that standard is measured with immunoblotting with the monoclonal antibody (SIGMA) at human fibronectin.
Result's (also seeing Fig. 2):
Compare with control treatment, at the cell (sampling in the 4th, 8 hour) that Xanifolia-Y handled, its fibronectin that is secreted in the cultivation reduces.Cellular form does not have obvious change, shows that cell does not have death.
Compare with control treatment sampling in the 24th hour, at the cell that Xanifolia-Y handled, its fibronectin that is secreted in the cultivation reduces more than 50%.But cellular form does not have obvious change, shows that cell does not have death.
Fibronectin excretory quantity (sampling in the 24th hour) is than high sampling in the 8th hour, illustrates that this period (24 hours) cell does not have death.
Experiment 4 (F4)
Method: ovarian cancer cell ES2 cultivates in the T-25 triangular flask of RPMI RPMI-1640 is arranged, and cultivates an evening.At 0 hour, the nutrient solution of cultured cells is changed the new substratum RPMI that contains xanifolia-Y (Y) (ultimate density 10ug/ml) or DMSO (D) cultivate.The 2nd, 4, got the content that the part nutrient solution is measured fibronectin in 8 and 24 hours.The content of fibronectin is measured with immunoblotting.In the time of 18 hours, cell viability is measured with mtt assay, and cultured cells was cultivated 1 hour with the RPMI nutrient solution that contains MTT again, and the formazan of formation dissolves among the DMSO and measures at 570nm with OD.
Result's (also seeing Fig. 2):
Cell above 95% is still living through MTT mensuration after handling 18 hours with Y.
Immunoblotting shows that the fibronectin that is secreted in the cultivation reduces.Scanning fibronectin Western bands of a spectrum (average 5 groups of blots) show that after handling 18 hours with Y, the fibronectin that is secreted in the cultivation reduces 40%.
Experiment 5 (F5):
Method: cell cultures and drug treating method are as described in the top experiment.At medication 7 or 24 hours sampling and measuring (immunoblotting) fibronectin content.24 hour cell vigor are sent out mensuration with MTT after the medication.
The result:
93% and 85% cell still lives through MTT mensuration after stabilizing 24 hours with Y processing 7.
After handling 7 hours, do not observe the fibronectin number change that is secreted in the substratum with Y.。But after handling 24 hours with Y, the fibronectin comparison and contrast group that is secreted in the cultivation reduces.Based on the viable cell of same quantity, relatively the fluorescence intensity of their immune bands of a spectrum (every MTT O.D. unit) 3 pairs of blots display fibers of scanning connect albumen bands and reduce 31%.The result shows that after handling 24 hours with Y, the fibronectin that cancer cells is secreted in the cultivation reduces 31%.
Experiment 6 (F7): Effects of Paclitaxel connects the proteic method that influences to ES2 cancer cells eccrine fiber: ovarian cancer cell ES2 cultivates in the T-25 triangular flask of RPMI RPMI-1640 is arranged, and cultivates an evening.Cultured cells is again with containing xanifolia-Y (Y) (10ug/ml), DMSO (D), or the new substratum RPMI cultivation of the Paclitaxel of 10or 50ng/ml (T10, or T50).Get the part nutrient solution after 24 hours and measure content (immunoblotting) mensuration of fibronectin.24 hour cell vigor are sent out mensuration with MTT after the medication.
The result:
Use Y, T10 compares with contrast (DMSO) with the cell that T50 handles,, handle after 24 hours, 87%, 94% and 91% cell lives respectively.Handle after 24 hours, measure cancer cells with (immunoblotting) and be secreted into fibronectin in the cultivation, the result is with Paclitaxel (T10, or T50) fibronectin of Chu Liing is respectively 105% or 97%, and the fibronectin that the cancer cells of handling with xanifolia-Y (Y) is secreted in the cultivation is 62% (reducing 38%).
Experiment 7 (F8): with Xanifolia-Y human body ovarian cancer cell Hey8A
Method:
Ovarian cancer cell Hey8A cultivates in the RPMI RPMI-1640, medication when 90% merges.Cultured cells is cultivated with the new substratum RPMI of the contrast DMSO (D) that contains xanifolia-Y (Y) (10,15 and 20ug/ml, Y1, Y2 and Y3) and no xanifolia-Y (Y) again.Sampling in 0 hour and got the content (immunoblotting mensuration) that the part nutrient solution is measured fibronectin at the 24th hour.After 24 hours, cell viability is measured with mtt assay, and cultured cells was cultivated 1 hour with the RPMI nutrient solution (5ml) that contains MTT again, and the formazan of formation dissolves in DMSO, measures at the 570nm wave band with OD.
Immunoblotting: culture (0.6ml) and damping fluid SDS (0.2ml) mix, and boil 3 minutes, put into sds gel.Sample (60ul/lane) is put into 6%SDS gel electrophoresis (100volts) 2 hours.Albumen changes nitrocellulose paper (100volts, 30 minutes) over to by electrophoresis.Immunoblotting respectively and first antibody (mouse anti-FN, specific to human FN, SIGMA F0916) is anti-hatches and second antibody (Anti-mouse IgG AP conjugated, Promega S3721) two anti-hatching.The immunity bands of a spectrum develop the color with BCIP/NBT developer system (Promega S3771).
The result:
Xanifolia-Y (Y) drug treating is after 24 hours, and the necrocytosis (floating) that concentration 15ug/ml and 20ug/ml handle can't continue experiment.The cell of concentration 10ug/ml and control treatment continues experiment.
MTT measures demonstration, and the cell growth that xanifolia-Y concentration 10ug/ml handles is 83% of contrast.
Immunoblotting shows, and contrast (D1) relatively, and the fluorescence intensity of the bands of a spectrum of the sample (Y1) that xanifolia-Y handles reduces a lot.
After the fluorescence intensity of average bands of a spectrum was corrected with MTT unit, the fluorescence intensity of control group was 1179, and the sample that xanifolia-Y handles is 366.With Dui Zhao Bi More, the fibronectin of the Hey8A emiocytosis 31% that xanifolia-Y handles, that is inhibiting rate is 69%.
Experiment 8 (F11): compounds X anifolia-Y suppresses the secretion of human body lung cancer (H460) cell fibronectin
Method: ask for an interview experiment 7.
The result: it is very strong that compound Y suppresses the effect of lung carcinoma cell (H460) eccrine fiber connection albumen, MTT measures demonstration, under concentration 20ug/ml, cell still lives, and compounds X anifolia-Y suppresses lung carcinoma cell (H460) eccrine fiber and connects albumen above 60%.
Experiment 9 (F 12): compounds X anifolia-Y suppresses the secretion of human bladder's cancer cells (HTB-9) fibronectin
Method: ask for an interview experiment 8.
The result:
MTT measures demonstration, and the cell growth that xanifolia-Y concentration 10ug/ml handles is the 77%-91% of contrast.
Immunoblotting shows, and contrast (D1) relatively, and the fluorescence intensity of the bands of a spectrum of the sample (Y1) that xanifolia-Y handles reduces a lot.
The fluorescence intensity of average bands of a spectrum is corrected back (being equivalent to the cell quality) with MTT unit, and the fluorescence intensity of fibronectin bands of a spectrum reduces about 50%.
The result shows that Xanifolia-Y (10ug/ml) suppresses fibronectin secretion 50%
Experiment 10 (F 13): handle the ES2 cell with beta-escin and Xanifolia-Y
Method: ask for an interview experiment 8.
The result:
MTT measures demonstration, xanifolia-Y10 (10ug/ml), and the cell growth that Es10 (10ug/ml) and Es20 (20ug/ml) handle is 89%, 90% and 82% of contrast.
Immunoblotting shows, and contrast (DMSO) relatively, and the fluorescence intensity of the bands of a spectrum of the sample that Es10 and Es20 handle is 93% and 52% of contrast, and the fluorescence intensity of the bands of a spectrum of the sample that xanifolia-Y handles is 51% of contrast.
The fluorescence intensity of average bands of a spectrum is corrected back (being equivalent to the cell quality) with MTT unit, and the fluorescence intensity of fibronectin bands of a spectrum reduces about 50%.
The result shows that Xanifolia-Y (10ug/ml) suppresses fibronectin secretion 49%, and Es10 and Es20 processing inhibition fibronectin are respectively 7% and 48%.
The result shows that the beta-escin can suppress the fibronectin secretion, but than a little less than the Xanifolia-Y.
Experiment 11 (F 14): with different Xanifolia-Ys compound treatment ES2 cells
Method: ask for an interview experiment 8. and finish two experiments (F14B and F14C).Each style is run five gels.
The result:
Except compd A KOH-Y (Y3 does not have angeloyl groups), other compound is the inhibition fibronectin excretory effect of showed different all.The AKOH-Y of concentration 80ug/ml (4 times to the concentration of other saponins) does not show the effect of any inhibition fibronectin excretory yet.
The ES2 cell ??β-ES-10 ??X-10 ??Y1-10 ??Y3-10 ??Y7-10 ??AKOH-80
Restraining effect % ??19 ??39 ??41 ??47 ??34 Do not have
Conclusion: saponin all has the ovarian cancer cell of inhibition ES2 eccrine fiber and connects proteic effect.
But this experimental result shows that it is most important that the acetylize that saponin carbon is 21,22 connects proteic restraining effect for the anticancer eccrine fiber.
Experiment 12 (F23): handle the ES2 cell with compound O54
Method: ask for an interview experiment 8.
The result: handle the ES2 cell with compound O54 (concentration 40ug/ml), unrestraint cancer cells eccrine fiber connects proteic restraining effect.
Experiment 13 (F24): handle the ES2 cell with compound Y0 and Y5
Method: ask for an interview experiment 8.
The result:
(1) compound Y5 and compound Y3 equally have the anticancer eccrine fiber and are connected proteic restraining effect (in 10ug/ml concentration, suppressing to reach 68%).
(2) compound Y0 suppress the effect of emiocytosis fibronectin than compound Y3 a little less than (Y0 suppresses 34% in 10ug/ml concentration).
(3) conclusion: Y0 has anticancer ES2 eccrine fiber with Y5 and is connected proteic restraining effect.
Experiment 14 (F25,26): handle the HepG2 cell with compound Ys
Method: ask for an interview experiment 8.
The result:
Under concentration 10ug/ml, compounds X, ES, Y0, Y1, Y3 have anticancer HepG2 eccrine fiber with Y5 and are connected proteic restraining effect (assigning 68% at 10ug/ml).Compound Y7, Ach (10ug/ml) and AKOH (80ug/ml) does not have or has slightly restraining effect (seeing the following form).
HepG2????????β????????X-10??Y0-10????Y1-10????Y3-10????Y7-10????ACH-Y-30
-ES-10
Restraining effect 44 42 40 33 48 10 21
％
Experiment 15 (F27,29): handle NCI-H460 (lung) cell with compound Ys
Method: ask for an interview experiment 8.
The results are shown in following table:
??H460 ??β-ES-20 ??X-20 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-20
Suppress to do Do not have ??37 ??22 ??13 ??19 ??18 ??28
Experiment 16 (F28,30): handle HTB-9 (bladder) cell with compound Ys
Method: ask for an interview experiment 8.
The results are shown in following table:
??HTB-9 ??β-ES-10 ??X-10 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-30
Restraining effect % ??47 ??38 ??32 ??50 ??51 ??60 Do not have
Experiment 17 (F31,32): handle T98G (brain) cell with compound Ys
Method: ask for an interview experiment 8.
The results are shown in following table:
??TG98G ??Y0-10 ??Y1-10 ?Y3-10 ??Y7-10 ??X-20 ??ES-20 ??ACH-20
Restraining effect % ??22 ??40 ?26 ??24 ??52 ??66 ??30
Experiment 18 (F33): with compound Ys treatment S K-MEL-5 (skin) cell
Method: ask for an interview experiment 8.
The results are shown in following table:
??SK-MEL-5 ??β-ES-20 ??X-20 ??Y0-10 ??Y1-10 ??Y3-10 ??Y7-10 ??ACH-Y-30
Restraining effect % ??17 ??15 ??27 ??10 ??11 Do not have ??21
Experiment 19 (F 20): with the mensuration of cell content and fibronectin behind the compound Y3 processing cancer cells
Method:
Ovarian cancer cell ES2 cultivates in the RPMI RPMI-1640, each T25 triangular flask 1.5 hundred ten thousand cell cultures 24 hours, cultured cells is cultivated with the new substratum RPMI that contains the xanifolia-Y3 (Y) of 10ug/ml concentration and the contrast DMSO that 2.5ul does not have xanifolia-Y (contrast D) more then.Get the part nutrient solution after 24 hours and measure the content (immunoblotting mensuration) of fibronectin.The cell suspension that sticks together is in 1ml SDS damping fluid (cell extract).
Immunoblotting: culture (0.6ml) and damping fluid SDS (0.2ml) mix, and cell extract boiled 3 minutes, put into sds gel then.Sample (80ul/lane) is put into 6-10%SDS gel electrophoresis (100volts) 2 hours.Albumen changes nitrocellulose membrane (100volts, 30 minutes) over to by electrophoresis.Digest cellulose film trace (blot) seals in the PBS that contains 5% skim-milk.Trace (blot) do antibody incubation (and first antibody, mouse-anti-FN, specific to human FN, SIGMA F0916, anti-beta actin, SIGMAA5316) and (second antibody, the IgG AP conjugated of anti-mouse, Promega S3721).The immunity bands of a spectrum develop the color with BCIP/NBT developer system (Promega S3771).The bands of a spectrum image of immunoblotting is taken pictures (an every gel 3-5 photo) with digital camera, and the fluorescence intensity of bands of a spectrum is determined with " Image J " software.As standard, measure the concentration numerical value of fibronectin with the concentration numerical value of the beta-Actin of cell.Mensuration compares its numerical value and control group (DMSO) through the content of emiocytosis fibronectin in substratum and in cell of the reason Over of compound Y place.
The result:
(1) emiocytosis handled of compound Y fibronectin in the substratum reduces 46% (content be contrast 54%).
(2) in the cell handled of compound Y fibronectin reduce 70% (content be contrast subtract 30%).
(3) after compound Y handles, the beta-actin concentration no change of cell.
The result proves that the expression and the resultant quantity of fibronectin in the cell have reduced.
Experiment 20: experimentation on animals
Method
Transplant the human body ovarian cancer cell for Athymic Nu/Nu mouse (2-3 month) subcutaneous (s.c.).Transplant after 5 days, mouse is divided into two groups (H and J), every group of two mouse.
The H group: 1-5 days and 8-10 days to mouse with Xanifolia-Y (i.p.) medicine, dosage 2.5mg/kg.
The J group is not given by mouseMedicine Xanifolia-Y
The result:
With Xanifolia-Y The H groupThe mouse tumour is 10mm (the 10th day) only.
Do not use Xanifolia-Y's J organizes mouseTumour reaches 18mm (the 10th day).
With the tumour of mouse of Xanifolia-Y than not with Xanifolia-Y little by 45% (the 10th day).
Experiment 21: experimentation on animals
Method
Athymic Nu/Nu mouse (5-6 week) is divided into 3 groups (O, P and Q), and every group of 5-6 props up mouse.The human body ovarian cancer cell is transplanted in all mouse abdominal cavities (i.p.).O organizes the not administration of mouse: O group mouse.P organizes mouse: at 4-8 days, 11-15 days, 18-22 days, 25-29 days, 32-36 days and 39-43 days, used Xanifolia-Y (i.p.) medicine, dosage 2.5mg/kg to P group mouse every day.
Q organizes mouse: at 10-15, and 18-22,25-29,32-36 and 39-43 days, used Xanifolia-Y (i.p.) medicine, dosage 2.5mg/kg to Q group mouse every day.
The result:
The mean survival time of the mouse of not administration is 24 days.The mouse mean survival time of administration in the 4th day is 58 days (prolonging life 141%).The mouse mean survival time of administration in the 10th day is 31 days (prolonging life 29%).
Experiment 22:Xanifolia-Y suppresses the effect of cytoadherence
Method: cancer cells ES2 or Hey8A cultivate in the T25 triangular flask that contains Xanifolia-Y (5ug/ml), 5 hours.The cell that is attached on bottle wall is shifted out by trypsin acting, and quantizes.
The result: and compare, 86 ± 4% ES2 cell and 67 ± 8% Hey8A cell are attached on bottle wall.It is alive that the cancer cells of culture medium culturing that contains the Xanifolia-Y of 5ug/ml surpasses 90% the cell that is attached on bottle wall, but the cancer cells of culture medium culturing that contains the Xanifolia-Y of 10ug/ml is no more than 10% cell and is attached on bottle wall, and much is dead cell.The result shows, the adhesion effect that Xanifolia-Y can anticancer.
Experiment 23:Xanifolia-Y increases the angiopoietin-2 of cancer cells ES2
(Angiopoietin-2) (ANGPT2) synthetic
Method: ovarian cancer cell ES2 cultivates in the RPMI RPMI-1640, each T75 triangular flask 4.5 hundred ten thousand cell cultures 24 hours, cultured cells xanifolia-Y 3 (5,10 and 15ug/ml, ultimate density) (Y3-5, Y3-10, Y3-15) or the DMSO (contrast D-10) of contrast handle.Culture was suspended in 1ml SDS damping fluid (cell extract) in 24 hours, and sample (80ul/lane) changes the 10%SDS gel over to, electrophoresis (100volts) 2 hours.Albumen changes nitrocellulose membrane over to by electrophoresis.Nitrocellulose membrane trace (blot) seals in the PBS that contains 5% skim-milk.Trace (blot) anti-hatching (and first antibody, goat resists-Ang2, SIGMA A0851) and two anti-hatch (second antibody, the anti-goat APconjugated of monkey, Promega V115A).The immunity bands of a spectrum develop the color with BCIP/NBT developer system (Promega S3771).
Result: on the Western trace, can observe the immune bands of a spectrum of angiogenin class 2 (Angiopoietin-2) in the extract of the cancer cells of handling with 15ug/ml Xanifolia-Y, but not observe with (ANGPT2) immune bands of a spectrum of the angiogenin class 2 (Angiopoietin-2) in the extract of the cancer cells of lower concentration Xanifolia-Y or control treatment.The result shows that handling cancer cells with Xanifolia-Y can increase cell content angiogenin class 2 (Angiopoietin-2) synthetic quantity (ANGPT2).This result has also obtained the affirmation of microarray research.
Claims (according to the modification of the 19th of treaty)
1. a composition is used to regulate Fibronectin or angiogenin and expresses, secretes or synthesize, and it is characterized in that described composition contains the compound of following structural formula, and this compound is separation, purifying or synthetic:
Figure FSB00000087887100011
Wherein R1 is H, hydroxyl, O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds; or derivatives thereof, wherein R2 is H, hydroxyl; the O-angeloyl groups, O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group; the O-alkyl, the two benzoyls of O-, O-benzoyl; the O-alkanoyl, the O-alkenoyl; the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base, O-acyl group; the O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof; R4 is CH2R6 or COR6, and wherein R6 is a chemical group, contains hydroxyl; the O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-; the O-benzoyl, O-alkanoyl, O-alkenoyl; the alkanoyl that O-phenmethyl alkyl replaces; the O-aromatic base, O-acyl group, O-heterogeneous ring compound; O-heterogeneous ring compound or heterocyclic aromatic compounds; or derivatives thereof, R3 are H or OH, and R8 is H or OH; OH particularly; R5 is hydrogen or sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi; rhamnosyl; pectinose, wood sugar, Fucose; Ah coughing up's sugar; altrose, gulose, idose; lyxose; seminose, ribose, sorbose; tagatose; talose, fructose, or uronic acid; glucuronic acid; galacturonic acid, or derivatives thereof, or their combination; CH3 particularly; at R1, among R2 and the R6, have at least two to contain following group: the O-angeloyl groups; O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group, O-alkyl, the two benzoyls of O-; the O-benzoyl; the O-alkanoyl, O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces; the O-aromatic base, O-acyl group, O-heterogeneous ring compound; O-heterogeneous ring compound or heterocyclic aromatic compounds; or derivatives thereof, or at R1, among R2 and the R4; at least one sugar chain by two in the following group substitute: angeloyl groups; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls; benzoyl, alkanoyl, alkenoyl; the alkanoyl that the phenmethyl alkyl replaces;, aromatic base, acyl group; heterogeneous ring compound; heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof
Here R4 is CH 2R6; R1 and R2 contain an angeloyl groups separately, or at R1, among R2 and the R6, have at least two to be the O-angeloyl groups, or at R1, a sugar chain that contains two angeloyl groups are arranged among R2 and the R6,
R3 is H or OH; R8 is H or OH,
R5 is hydrogen or sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination, the R9 in the compound wherein, R10, R11, R12, R13, R14, R15 are group: CH independently 3, CH 2OH, CHO, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic compounds, CH 2The O aromatic base, CH 2The O-heterogeneous ring compound, CH 2The O-heterocyclic aromatic base, alkyl, hydroxyl or ethanoyl, in another case; R5 is that sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, pectinose, or uronic acid; glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.
2. composition as claimed in claim 1; it is characterized in that at least one is the O-ethanoyl among the R1 and R2 in the described composition, the O-angeloyl groups, O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group; two benzoyls of O-and O-benzoyl, or at least one is a sugar chain among R1 and the R2, and this sugar chain is replaced by following two groups: ethanoyl; angeloyl groups; along root of Dahurian angelica acyl group, squaw weed acyl group, two benzoyls or benzoyl; R5 is hydrogen or sugar chain; this sugar chain contains glucose, grape semi-lactosi, Arabic glucose; with its derivative; this derivative comprises acid, ester or salt
3. composition as claimed in claim 1, it is characterized in that described adjusting Fibronectin comprises the protein of fibronectin, integrin family, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen, its regulating effect comprises minimizing, suppress and excitation
4. composition as claimed in claim 1, it is characterized in that described adjusting Fibronectin comprises expression, the secretion or synthetic that reduces fibronectin, thereby the transfer of anticancer or growth, wherein said cancer cells comprise mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma.
5. composition as claimed in claim 1, it is characterized in that regulating the expression of angiogenin, comprising angiogenin 1, angiogenin 2, angiogenin 3, angiogenin 4, angiogenin 5, angiogenin 6 and angiogenin 7, angiogenin-class 1, angiogenin-class 2, angiogenin-class 3, angiogenin-class 4, angiogenin-class 5, angiogenin-class 6 and angiogenin-class 7, here said regulating effect comprises positive and negative regulating effect, the expression that wherein excites angiogenin 2 is to suppress vasculogenesis, and the expression that suppresses angiogenin 1 is to suppress vasculogenesis, and application wherein comprises the expression of inhibition angiogenin-class 1 and angiogenin-class 4.
6. composition as claimed in claim 1 is characterized in that described composition is to contain following compound:
A) extraction separation or synthetic has a chemical structure Xanifolia (Y),
Figure F66007641150127000C000031
Title: 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
B) extraction separation or synthetic has a chemical structure Xanifolia (Y1),
Figure F66007641150127000C000032
Title: 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O (3; acyl group is returned by the two parties of 4-)-α-L-rhamnosyl pyrans acyl group-22-O-ethanoyl-3 β; 16 α; 21 β; 22 α; 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
C) extraction separation or synthetic has a chemical structure Xanifolia (Y2),
Figure F66007641150127000C000041
Title is 3-0-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin
D) extraction separation or synthetic has a chemical structure Xanifolia (Y8),
Figure F66007641150127000C000042
Title is 3-0-[β-glucose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β, 16 α return in the two parties of 22-O-; 21 β, 22 α, 24 β; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
E) extraction separation or synthetic has a chemical structure Xanifolia (Y9),
Figure F66007641150127000C000043
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28-O-ethanoyl-3 β; 16 α; 21 β; 22 α; 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
F) extraction separation or synthetic has a chemical structure Xanifolia (Y10),
Figure F66007641150127000C000051
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns in the two parties of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin,
G) extraction separation or synthetic has a chemical structure Xanifolia (Y0),
Figure F66007641150127000C000052
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
H) extraction separation or synthetic has a chemical structure Xanifolia (X),
Figure F66007641150127000C000053
Title is 3-0-{[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyranoside butyl ester }-the 21-0-ethanoyl, acyl group-3 β, 16 α return in 22-O-party; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
I) extraction separation or synthetic has a chemical structure (Y7),
Figure F66007641150127000C000061
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-28-O-(2-first butyryl radicals)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
J) extraction separation or synthetic has a chemical structure (ACH-Y):
Figure F66007641150127000C000062
K) extraction separation or synthetic has a chemical structure:
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-pectinose furans acyl group (1 → 4)-beta-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-ethanoyl-3 β; 16 α, 21 β, 22 α; 24 β, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
L) extraction separation or synthetic has a chemical structure:
Figure F66007641150127000C000071
M) extraction separation or synthetic has a chemical structure:
Figure F66007641150127000C000072
7. a compound is regulated application in the medicine of Fibronectin in the cell or angiogenin in preparation, comprises compound or its salt class or the ester class handling described cell and contain the following structure of effective dose, and this compound is separation, purifying or synthetic:
Wherein R1 is H, hydroxyl, and the O-angeloyl groups, O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group, O-alkyl, the two benzoyls of O-, O-benzoyl; the O-alkanoyl, O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound, O-heterocyclic aromatic compounds and sugar chain; this sugar chain is replaced by two following radicals: ethanoyl, angeloyl groups, Cis root of Dahurian angelica acyl group; the squaw weed acyl group, alkyl, two benzoyls; benzoyl, R2 are hydroxyls, the O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound; O-heterocyclic aromatic compounds and O-sugar chain, this sugar chain is replaced by two following radicals: ethanoyl, angeloyl groups; Cis root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl and derivative thereof
R4 is CH 2R6 or COR6, wherein R6 is in the following groups one: hydroxyl, O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound and O-heterocyclic aromatic compounds; R1 here has at least one to be in the following groups one among R2 and the R6: the O-angeloyl groups, and O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group, O-alkyl, the two benzoyls of O-; the O-benzoyl; the O-alkanoyl, O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces; the O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound; O-heterocyclic aromatic compounds and its derivative
R3 is hydrogen or OH; R8 is hydrogen or OH,
R5 is hydrogen or sugar chain, and this sugar chain is a glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination, the R9 in the compound wherein, R10, R11, R12, R13, R14, R15 are group: CH independently 3, CH 2OH, CHO, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic base, CH 2The O-aromatic base, CH 2The O-heterogeneous ring compound, CH 2The O-heterocyclic aromatic base, alkyl, hydroxyl or ethanoyl, CH 3Be optimal selection.
8. application as claimed in claim 7 is characterized in that at least one is the O-ethanoyl among the R1 and R2 in the described compound, the O-angeloyl groups; O-Cis root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-; the O-benzoyl, or at least one is a sugar chain among R1 and the R2, and this sugar chain is by two ethanoyl that following radicals replaces; angeloyl groups; Cis root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls; benzoyl, R5 are hydrogen or sugar chain, and this sugar chain is by glucose; semi-lactosi; pectinose and its derivative are formed, and this derivative is acid, ester class and salt.
9. application as claimed in claim 7, it is characterized in that regulating expression, the secretion or synthetic of Fibronectin, protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen comprising fibronectin, integrin family, its regulating effect comprises minimizing, suppresses and excitation.
10. application as claimed in claim 7, it is characterized in that regulating the expression of Fibronectin, secretion or synthetic, comprising fibronectin, the protein of integrin family, myosin, vitronectin, collagen protein, ln, the glycosylation cell surface protein, saccharan albumen, the calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen, thereby the transfer of anticancer or growth, wherein said cancer cells comprises mammary cancer, the white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, the nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma.
11. application as claimed in claim 7, it is characterized in that regulating the expression of angiogenin, comprising angiogenin 1, angiogenin 2, angiogenin 3, angiogenin 4, angiogenin 5, angiogenin 6 and angiogenin 7, angiogenin-class 1, angiogenin-class 2, angiogenin-class 3, angiogenin-class 4, angiogenin-class 5, angiogenin-class 6 and angiogenin-class 7, here said regulating effect comprises positive and negative regulating effect, the expression that wherein excites angiogenin 2 is to suppress vasculogenesis, and the expression that suppresses angiogenin 1 is to suppress vasculogenesis, and application wherein comprises the expression of inhibition angiogenin-class 1 and angiogenin-class 4.
12. application as claimed in claim 7 is characterized in that expression, secretion or the synthetic with following compound medicament adjusting Fibronectin or angiogenin used:
A) extraction separation or synthetic has a chemical structure Xanifolia (Y),
Figure F66007641150127000C000091
Title: 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
B) extraction separation or synthetic has a chemical structure Xanifolia (Y1),
Title is 3-0-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin
C) extraction separation or synthetic has a chemical structure Xanifolia (Y2),
Figure F66007641150127000C000102
Title is 3-0-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin
D) extraction separation or synthetic has a chemical structure Xanifolia (Y8),
Figure F66007641150127000C000103
Title is 3-0-[β-glucose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β, 16 α return in the two parties of 22-O-; 21 β, 22 α, 24 β; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
E) extraction separation or synthetic has a chemical structure Xanifolia (Y9),
Figure F66007641150127000C000111
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28-O-ethanoyl-3 β; 16 α; 21 β; 22 α; 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
F) extraction separation or synthetic has a chemical structure Xanifolia (Y10),
Figure F66007641150127000C000112
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns in the two parties of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin,
G) extraction separation or synthetic has a chemical structure Xanifolia (Y0),
Figure F66007641150127000C000113
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
H) extraction separation or synthetic has a chemical structure Xanifolia (X),
Figure F66007641150127000C000121
Title is 3-0-{[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyranoside butyl ester }-the 21-0-ethanoyl, acyl group-3 β, 16 α return in 22-O-party; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
I) extraction separation or synthetic has a chemical structure (Y7),
Figure F66007641150127000C000122
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-28-O-(2-first butyryl radicals)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
J) extraction separation or synthetic has a chemical structure (ACH-Y):
K) extraction separation or synthetic has a chemical structure:
Figure F66007641150127000C000131
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-pectinose furans acyl group (1 → 4)-beta-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-ethanoyl-3 β; 16 α, 21 β, 22 α; 24 β, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
L) extraction separation or synthetic has a chemical structure:
Figure F66007641150127000C000132
M) extraction separation or synthetic has a chemical structure:
Figure F66007641150127000C000133
13. the instructions of taking of the composition of claim the 1, it is intravenous injection, vein drips slide, peritoneal injection or oral, here, vein drip: per kilogram consumption 0.05-0.2mg, be dissolved in 10% the glucose solution of 250ml or 0.9% sodium chloride solution of 250ml, intravenous injection: every day per kilogram consumption 0.05-0.2mg, be dissolved in 10% glucose solution or 0.9% sodium chloride solution of 10-20ml, the vein drip: every day per kilogram consumption 0.1-0.2mg, be dissolved in 10% the glucose solution of 250ml or 0.9% sodium chloride solution of 250ml, intravenous injection: every day per kilogram consumption 0.1-0.2mg, be dissolved in 10% glucose solution or 0.9% sodium chloride solution of 10-20ml, also can peritoneal injection: every day per kilogram consumption 2.5-0.2mg, be dissolved in 10% glucose solution or 0.9% sodium chloride solution, this kind also can be oral as the composition of medicine, Mammals dosage per kilogram 1-10mg, this kind is as the composition palatable clothes of medicine, dosage per kilogram 1-10mg 10-30mg, 30-60mg or 60-90mg, this described composition is used as medicine intravenous injection or vein drip, Mammals per kilogram consumption 0.01-0.10mg, 0.1-0.20mg, 0.2-0.4mg, or 0.4-0.6mg, the Mammals peritoneal injection: every day per kilogram consumption 1-3mg, 3-5mg, 4-6mg, or 6-10mg.
14. the application of compound in the medicine of preparation adjusting cellular gene expression is characterized in that described method is with the described compound of claim the 1-6 item, the drug treating cell of its esters and the preparation of ester class, described compound is to separate, purifying or synthetic, described gene are gene as described below: ABL2, ADAMTS1, AKR1C3, AMIGO2, ANGPT2, ANKRD11, AP2B1, APEH, APLP2, ARL10C, ARMC4, ARMCX1, ARMCX6, ARNTL2, ARNTL2, ATF3, ATP6V0E, ATP6V1B2, ATP6V1C1, ATP6V1C1, BCL2A1, BCL6, BRI3, BTD, C14orf109, C14orf78, C17orf32, C6orf65, C9orf10, C9orf103, CAD, CAV1, CAV2, CBLL1, CCL20, CD33L3, CEBPB, CEP4, CFH/ //CFHL1, CHRDL1, CITED2, CITED2, CLDN14, CLN8, CLTA, CNAP1, COG6, COL18A1, COL4A2, COL5A1, COL5A2, COL6A3, COPG, CPM, CPNE3, CPSF1, CSRP2BP, CSTB, CTNS, CXCL2, DDB1, DDIT3, DDX20, DKFZP564I 1171, DKFZP586J0619, DUSP 10, and DUSP 10, DYRK3, EEF2K, EFEMP1, EMP1, EVC, EVI2A, EXT2, FAM62A, FER1L3, FLJ14466, FLNA, FN1, FN1, GANAB, GDF15, GEM, GNPDA1, GPAA1, GPC6, GPNMB, GPNMB, GUSB, H2AFV, H2AFV, HDAC9, HDLBP, HECW2, HMGA2, HMOX1, HSDL2, HSPBAP1, HSPC196, HYOU1, IDS, IGFBP3, IKBKAP, INSIG1, IPO4, IRS2, JAG1, KDELR3, KIAA0251, KIAA0586, KIAA1211, KIAA1462, KIAA1706, KIAA1754, KRT18, KRT7, KRTAP4-7, LAMP2, LEPR, LEPREL1, LHFPL2, LIF, LOC286044, LOC339229, LOC90693, LRRC8E, MAFG, MAGED2, MCTP1, MGC16291, MGC19764, MGC5618, MRPS30, MRPS31, MTERFD3, MYH9, NAGA, NAV2, NCSTN, NEK9, NEU1, NFKBIZ, NMT2, NPC2, NSUN5C, NTNG1, NUP188, OACT2, OS9, P4HA1, P8, PALM2-AKAP2, PALM2-AKAP2, PARVA, PBX2, PDE4DIP, PDIA4, PDIA6, PEG10, PHF19, PIK4CA, PLEKHM1, PLOD1, PLOD2, PPP1R15A, PPP1R15A, PRKDC, PRSS23, PRSS23, PSEN2, PSMD1, PTPRF, PTPRJ, RAB32, RAB9A, RG9MTD1, RGS4, RHOQ, RND3, RNF25, RNPEP/ //UBE2V1/ //Kua/ //Kua-UEV, RNU17D, ROBO4, RRAGC, RRS1, SEC31L1, SERPINB2, SERPINB7, SESN2, SGEF, SGSH, SKIV2L, SLC25A21, SLC35A3, SLC3A2, SMARCA1, SNAPC1, SNF1LK, SPOCD1, SPTAN1, SQSTM1, ST3GAL6, STC2, STX3A, TFPI2, TFPI2, TGFBI, TGM2, THRAP1, TLN1, TMEM60, TNFAIP3, TRIB3, TRIO, TSC2, UAP1L1, UBAP2L, UPP1, URB, USP11, USP5, VDR, WDR4, YTHDF2, ZCCHC9, ZDHHC20, ZFHX1B, ZNF185, ZNF278, ZNF690, ZNF697; Or described gene is to select gene as described below: FN1, ITGAV, LAMA4, LAMB2, LAMC1, LAMB1, LAMB1, LAMA4, LAMA5, LAMC1, LAMA2, LAMB1, LAMA3, SCAMP1, TICAM2, SCAMP1, TICAM2, SCAMP1, SCAMP1, CAMK2B, DL1, ICAM3, CEECAM1, ICAM5, SCAMP1, CAMK1G, CAMSAP1, MCAM, CAMTA1, CKN1, ALCAM, DCAMKL2, CEACAM3, CAMK2D, CAMK2B, SCAMP5, CAMK4, NCAM1, CAMK2G, MYH9, MYH10, MYO1D, MYO5A, MYLK, MYO6, MYO5A, MYO1C, MYLK, MYO6, MYLC2PL, MYO10, MYO6, TPM3, MYO1C, BECN1, MYO1E, TPM3, M-RIP, MYO1B, MYO10, MYO5A, M-RIP, MYO10, MYL6, MYOHD1, BECN1, TPM4, MYLK, MYH10, MYOHD1, LOC221875, LOC402643, MYO15B, LOC129285, MYH11, MYO1B, MYO1C, MYO9B, CDH13, CTNNAL1, CDH13, CDH12, CTNNB1, CDH5, CTNND1, CDH2, CTNNA1, CDH2, PCDHB16, CTNNA1, CELSR2, PCDHB6, PCDHB7, CTNND2, PCDHGC3, PCDHGB4, PCDHGA8, PCDHGA12, PCDHGC5, PCDHGC4, PCDHGB7, PCDHGB6, PCDHGB5, PCDHGB3, PCDHGB2, PCDHGB1, PCDHGA11, PCDHGA10, PCDHGA9, PCDHGA7, PCDHGA6, PCDHGA5, PCDHGA4, PCDHGA3, PCDHGA2, PCDHGA1, CTNND1, CDH23, PCDHB12, PCDHB10, PCDH18, CDH20, PCDH9, PCDHGA12, PCDHGA11, PCDHGA10, PCDHGA6, PCDHGA5, PCDHGA3, PCDH7, CDH18, CDH6, CCBE1, COL10A1, COL12A1, COL13A1, COL18A1, COL1A1, COL21A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL9A1, MMP9, P4HA1, P4HA2, P4HB, PCOLCE, PCOLCE2, PCOTH, PLOD1, PLOD2, PLOD3, CIB1, ILK, ITGA2, ITGA3, ITGA4, ITGA6, ITGAV, ITGB1, ITGB1BP1, ITGB2, ITGB5, ITGBL1, TNC, EMILIN1, ICAM1, HSPG2, HPSE, HS2ST1, SDC2.

Claims (14)

1. a composition is used to regulate Fibronectin or angiogenin and expresses, secretes or synthesize, and it is characterized in that described composition contains the compound of following structural formula, and this compound is separation, purifying or synthetic:
Figure FSB00000087887000011
Wherein R1 is H, hydroxyl, O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds; or derivatives thereof, wherein R2 is H, hydroxyl; the O-angeloyl groups, O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group; the O-alkyl, the two benzoyls of O-, O-benzoyl; the O-alkanoyl, the O-alkenoyl; the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base, O-acyl group; the O-heterogeneous ring compound, O-heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof; R4 is CH2R6 or COR6, and wherein R6 is a chemical group, contains hydroxyl; the O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-; the O-benzoyl, O-alkanoyl, O-alkenoyl; the alkanoyl that O-phenmethyl alkyl replaces; the O-aromatic base, O-acyl group, O-heterogeneous ring compound; O-heterogeneous ring compound or heterocyclic aromatic compounds; or derivatives thereof, R3 are H or OH, and R8 is H or OH; OH particularly; R5 is hydrogen or sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi; rhamnosyl; pectinose, wood sugar, Fucose; Ah coughing up's sugar; altrose, gulose, idose; lyxose; seminose, ribose, sorbose; tagatose; talose, fructose, or uronic acid; glucuronic acid; galacturonic acid, or derivatives thereof, or their combination; CH3 particularly; at R1, among R2 and the R6, have at least two to contain following group: the O-angeloyl groups; O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group, O-alkyl, the two benzoyls of O-; the O-benzoyl; the O-alkanoyl, O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces; the O-aromatic base, O-acyl group, O-heterogeneous ring compound; O-heterogeneous ring compound or heterocyclic aromatic compounds; or derivatives thereof, or at R1, among R2 and the R4; at least one sugar chain by two in the following group substitute: angeloyl groups; along root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls; benzoyl, alkanoyl, alkenoyl; the alkanoyl that the phenmethyl alkyl replaces;, aromatic base, acyl group; heterogeneous ring compound; heterogeneous ring compound or heterocyclic aromatic compounds, or derivatives thereof
Here R4 is CH 2R6; R1 and R2 contain an angeloyl groups separately, or at R1, among R2 and the R6, have at least two to be the O-angeloyl groups, or at R1, a sugar chain that contains two angeloyl groups are arranged among R2 and the R6,
R3 is H or OH; R8 is H or OH,
R5 is hydrogen or sugar chain, and sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination, the R9 in the compound wherein, R10, R11, R12, R13, R14, R15 are group: CH independently 3, CH 2OH, CHO, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic compounds, CH 2The O aromatic base, CH 2The O-heterogeneous ring compound, aromatic base, alkyl, hydroxyl or ethanoyl, in another case; R5 is that sugar chain contains one or more following sugar and uronic acid at least: glucose, semi-lactosi, pectinose, or uronic acid; glucuronic acid, galacturonic acid, or derivatives thereof, or their combination.
2. composition as claimed in claim 1; it is characterized in that at least one is the O-ethanoyl among the R1 and R2 in the described composition, the O-angeloyl groups, O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group; two benzoyls of O-and O-benzoyl, or at least one is a sugar chain among R1 and the R2, and this sugar chain is replaced by following two groups: ethanoyl; angeloyl groups; along root of Dahurian angelica acyl group, squaw weed acyl group, two benzoyls or benzoyl; R5 is hydrogen or sugar chain; this sugar chain contains glucose, grape semi-lactosi, Arabic glucose; with its derivative; this derivative comprises acid, ester or salt
3. composition as claimed in claim 1, it is characterized in that described adjusting Fibronectin comprises the protein of fibronectin, integrin family, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen, its regulating effect comprises minimizing, suppress and excitation
4. composition as claimed in claim 1, it is characterized in that described adjusting Fibronectin comprises expression, the secretion or synthetic that reduces fibronectin, thereby the transfer of anticancer or growth, wherein said cancer cells comprise mammary cancer, white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma.
5. composition as claimed in claim 1, it is characterized in that regulating the expression of angiogenin, comprising angiogenin 1, angiogenin 2, angiogenin 3, angiogenin 4, angiogenin 5, angiogenin 6 and angiogenin 7, angiogenin-class 1, angiogenin-class 2, angiogenin-class 3, angiogenin-class 4, angiogenin-class 5, angiogenin-class 6 and angiogenin-class 7, here said regulating effect comprises positive and negative regulating effect, the expression that wherein excites angiogenin 2 is to suppress vasculogenesis, and the expression that suppresses angiogenin 1 is to suppress vasculogenesis, and application wherein comprises the expression of inhibition angiogenin-class 1 and angiogenin-class 4.
6. composition as claimed in claim 1 is characterized in that described composition is to contain following compound:
A) extraction separation or synthetic has a chemical structure Xanifolia (Y),
Figure F2008800120650C00031
Title: 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
B) extraction separation or synthetic has a chemical structure Xanifolia (Y1),
Figure F2008800120650C00032
Title: 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-O (3; acyl group is returned by the two parties of 4-)-α-L-rhamnosyl pyrans acyl group-22-O-ethanoyl-3 β; 16 α; 21 β; 22 α; 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
C) extraction separation or synthetic has a chemical structure Xanifolia (Y2),
Figure F2008800120650C00041
Title is 3-0-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin
D) extraction separation or synthetic has a chemical structure Xanifolia (Y8),
Figure F2008800120650C00042
Title is 3-0-[β-glucose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β, 16 α return in the two parties of 22-O-; 21 β, 22 α, 24 β; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
E) extraction separation or synthetic has a chemical structure Xanifolia (Y9),
Figure F2008800120650C00043
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28-O-ethanoyl-3 β; 16 α; 21 β; 22 α; 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
F) extraction separation or synthetic has a chemical structure Xanifolia (Y10),
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns in the two parties of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin,
G) extraction separation or synthetic has a chemical structure Xanifolia (Y0),
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
H) extraction separation or synthetic has a chemical structure Xanifolia (X),
Figure F2008800120650C00053
Title is 3-0-{[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyranoside butyl ester }-the 21-0-ethanoyl, acyl group-3 β, 16 α return in 22-O-party; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
I) extraction separation or synthetic has a chemical structure (Y7),
Figure F2008800120650C00061
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-28-O-(2-first butyryl radicals)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
J) extraction separation or synthetic has a chemical structure (ACH-Y):
Figure F2008800120650C00062
K) extraction separation or synthetic has a chemical structure:
Figure F2008800120650C00063
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-pectinose furans acyl group (1 → 4)-beta-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-ethanoyl-3 β; 16 α, 21 β, 22 α; 24 β, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
7. method of regulating Fibronectin in the cell or angiogenin comprises the compound of the following structure of handling described cell and effective dose, and this compound is separation, purifying or synthetic:
Figure F2008800120650C00071
Wherein R1 is H, hydroxyl, and the O-angeloyl groups, O-is along root of Dahurian angelica acyl group; O-squaw weed acyl group, O-alkyl, the two benzoyls of O-, O-benzoyl; the O-alkanoyl, O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound, O-heterocyclic aromatic compounds and sugar chain; this sugar chain is replaced by two following radicals: ethanoyl, angeloyl groups, Cis root of Dahurian angelica acyl group; the squaw weed acyl group, alkyl, two benzoyls; benzoyl, R2 are hydroxyls, the O-angeloyl groups; O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-, O-benzoyl, O-alkanoyl; the O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base; the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound; O-heterocyclic aromatic compounds and O-sugar chain, this sugar chain is replaced by two following radicals: ethanoyl, angeloyl groups; Cis root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls, benzoyl and derivative thereof
R4 is CH 2R6 or COR6, wherein R6 is in the following groups one: hydroxyl, O-angeloyl groups, O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl, the two benzoyls of O-, O-benzoyl, O-alkanoyl, the O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, O-aromatic base, the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound and O-heterocyclic aromatic compounds, R1 here has at least one to be in the following groups one among R2 and the R6: the O-angeloyl groups, and O-is along root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl, the two benzoyls of O-, the O-benzoyl, the O-alkanoyl, O-alkenoyl, the alkanoyl that O-phenmethyl alkyl replaces, the O-aromatic base, the O-acyl group, O-heterogeneous ring compound, O-heterogeneous ring compound, O-heterocyclic aromatic compounds and its derivative, R3 is hydrogen or OH; R8 is hydrogen or OH,
R5 is hydrogen or sugar chain, and this sugar chain is a glucose, semi-lactosi, rhamnosyl, pectinose, wood sugar, Fucose, Ah coughing up's sugar, altrose, gulose, idose, lyxose, seminose, ribose, sorbose, tagatose, talose, fructose, or uronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or their combination, the R9 in the compound wherein, R10, R11, R12, R13, R14, R15 are group: CH independently 3, CH 2OH, CHO, COOH, COO-alkyl, COO-aromatic base, COO-heterogeneous ring compound, COO-heterocyclic aromatic base, CH 2The O-aromatic base, CH 2The O-heterogeneous ring compound, CH 2The O-heterocyclic aromatic base, alkyl, hydroxyl or ethanoyl, CH 3Be optimal selection.
8. method as claimed in claim 7 is characterized in that at least one is the O-ethanoyl among the R1 and R2 in the described compound, the O-angeloyl groups; O-Cis root of Dahurian angelica acyl group, O-squaw weed acyl group, O-alkyl; the two benzoyls of O-; the O-benzoyl, or at least one is a sugar chain among R1 and the R2, and this sugar chain is by two ethanoyl that following radicals replaces; angeloyl groups; Cis root of Dahurian angelica acyl group, squaw weed acyl group, alkyl; two benzoyls; benzoyl, R5 are hydrogen or sugar chain, and this sugar chain is by glucose; semi-lactosi; pectinose and its derivative are formed, and this derivative is acid, ester class and salt.
9. method as claimed in claim 7, it is characterized in that regulating expression, the secretion or synthetic of Fibronectin, protein, myosin, vitronectin, collagen protein, ln, glycosylation cell surface protein, saccharan albumen, calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen comprising fibronectin, integrin family, its regulating effect comprises minimizing, suppresses and excitation.
10. method as claimed in claim 7, it is characterized in that regulating the expression of Fibronectin, secretion or synthetic, comprising fibronectin, the protein of integrin family, myosin, vitronectin, collagen protein, ln, the glycosylation cell surface protein, saccharan albumen, the calcium conglutination element, heparin albumen, tough sticking element, cell adhesion molecule CAM, adhesion molecule CD54, elastin and FAK albumen, thereby the transfer of anticancer or growth, wherein said cancer cells comprises mammary cancer, the white corpuscle cancer, liver cancer, mammary cancer, bladder cancer, prostate cancer, skin carcinoma, osteocarcinoma, the cancer of the brain, leukemia, lung cancer, colorectal carcinoma, the nervus centralis cancer, melanoma, cervical cancer and uterus carcinoma.
11. method as claimed in claim 7, it is characterized in that regulating the expression of angiogenin, comprising angiogenin 1, angiogenin 2, angiogenin 3, angiogenin 4, angiogenin 5, angiogenin 6 and angiogenin 7, angiogenin-class 1, angiogenin-class 2, angiogenin-class 3, angiogenin-class 4, angiogenin-class 5, angiogenin-class 6 and angiogenin-class 7, here said regulating effect comprises positive and negative regulating effect, the expression that wherein excites angiogenin 2 is to suppress vasculogenesis, and the expression that suppresses angiogenin 1 is to suppress vasculogenesis, and application wherein comprises the expression of inhibition angiogenin-class 1 and angiogenin-class 4.
12. method as claimed in claim 7 is characterized in that expression, secretion or the synthetic with following compound medicament adjusting Fibronectin or angiogenin used:
A) extraction separation or synthetic has a chemical structure Xanifolia (Y),
Figure F2008800120650C00091
Title: 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
B) extraction separation or synthetic has a chemical structure Xanifolia (Y1),
Figure F2008800120650C00092
Title is 3-0-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin
C) extraction separation or synthetic has a chemical structure Xanifolia (Y2),
Figure F2008800120650C00093
Title is 3-0-[β-D-glucose pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3) β-D-glucuronic acid pyrans acyl group-21, acyl group-3 β, 15 α return in the two parties of 22-O-; 16 α, 21 β, 22 α; 24 β, 28-seven hydroxyls olea-12-alkene pentacyclic triterpenoid saponin
D) extraction separation or synthetic has a chemical structure Xanifolia (Y8),
Figure F2008800120650C00101
Title is 3-0-[β-glucose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β, 16 α return in the two parties of 22-O-; 21 β, 22 α, 24 β; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
E) extraction separation or synthetic has a chemical structure Xanifolia (Y9),
Figure F2008800120650C00102
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21-O-(3; acyl group is returned by the two parties of 4-)-α-rhamnosyl pyrans acyl group-28-O-ethanoyl-3 β; 16 α; 21 β; 22 α; 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
F) extraction separation or synthetic has a chemical structure Xanifolia (Y10),
Title is a 3-0-[beta galactose pyrans acyl group (1 → 2)]-α-pectinose furans acyl group (1 → 3)-beta-glucuronic acid pyrans acyl group-21, acyl group-3 β returns in the two parties of 22-O-, 16 α, 21 β, 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin,
G) extraction separation or synthetic has a chemical structure Xanifolia (Y0),
Figure F2008800120650C00111
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-(2-first propionyl)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
H) extraction separation or synthetic has a chemical structure Xanifolia (X),
Title is 3-0-{[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyranoside butyl ester }-the 21-0-ethanoyl, acyl group-3 β, 16 α return in 22-O-party; 21 β; 22 α, 28-penta hydroxy group olea-12-alkene pentacyclic triterpenoid saponin
I) extraction separation or synthetic has a chemical structure (Y7),
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-α-L-arabinose furans acyl group (1 → 3)-β-D-glucuronic acid pyrans acyl group-21-0-party returns acyl group-28-O-(2-first butyryl radicals)-3 β; 15 α; 16 α; 21 β; 22 α; 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin
J) extraction separation or synthetic has a chemical structure (ACH-Y):
Figure F2008800120650C00121
K) extraction separation or synthetic has a chemical structure:
Figure F2008800120650C00122
Title is 3-0-[β-D-semi-lactosi pyrans acyl group (1 → 2)]-β-pectinose furans acyl group (1 → 4)-beta-glucuronic acid pyrans acyl group-21-0-party returns acyl group-22-O-ethanoyl-3 β; 16 α, 21 β, 22 α; 24 β, 28-hexahydroxy-olea-12-alkene pentacyclic triterpenoid saponin.
13. the instructions of taking of the described composition of claim 1, it is intravenous injection, vein drips slide, peritoneal injection or oral, here, vein drip: per kilogram consumption 0.05-0.2mg, be dissolved in 10% the glucose solution of 250ml or 0.9% sodium chloride solution of 250ml, intravenous injection: every day per kilogram consumption 0.05-0.2mg, be dissolved in 10% glucose solution or 0.9% sodium chloride solution of 10-20ml, the vein drip: every day per kilogram consumption 0.1-0.2mg, be dissolved in 10% the glucose solution of 250ml or 0.9% sodium chloride solution of 250ml, intravenous injection: every day per kilogram consumption 0.1-0.2mg, be dissolved in 10% glucose solution or 0.9% sodium chloride solution of 10-20ml, also can peritoneal injection: every day per kilogram consumption 2.5-0.2mg, be dissolved in 10% glucose solution or 0.9% sodium chloride solution, this kind also can be oral as the composition of medicine, Mammals dosage per kilogram 1-10mg, this kind is as the composition palatable clothes of medicine, dosage per kilogram 1-10mg 10-30mg, 30-60mg or 60-90mg, this described composition is used as medicine intravenous injection or vein drip, Mammals per kilogram consumption 0.01-0.10mg, 0.1-0.20mg, 0.2-0.4mg, or 0.4-0.6mg, the Mammals peritoneal injection: every day per kilogram consumption 1-3mg, 3-5mg, 4-6mg, or 6-10mg.
14. a method of regulating cellular gene expression is characterized in that described method is with the described compound of claim the 1-5 item, the drug treating cell of its esters and the preparation of ester class, here said gene is gene as described below: ABL2, ADAMTS1, AKR1C3, AMIGO2, ANGPT2, ANKRD11, AP2B1, APEH, APLP2, ARL10C, ARMC4, ARMCX1, ARMCX6, ARNTL2, ARNTL2, ATF3, ATP6V0E, ATP6V1B2, ATP6V1C1, ATP6V1C1, BCL2A1, BCL6, BRI3, BTD, C14orf109, C14orf78, C17orf32, C6orf65, C9orf10, C9orf103, CAD, CAV1, CAV2, CBLL1, CCL20, CD33L3, CEBPB, CEP4, CFH/ //CFHL1, CHRDL1, CITED2, CITED2, CLDN14, CLN8, CLTA, CNAP1, COG6, COL18A1, COL4A2, COL5A1, COL5A2, COL6A3, COPG, CPM, CPNE3, CPSF1, CSRP2BP, CSTB, CTNS, CXCL2, DDB1, DDIT3, DDX20, DKFZP564I1171, DKFZP586J0619, DUSP10, DUSP10, DYRK3, EEF2K, EFEMP1, EMP1, EVC, EVI2A, EXT2, FAM62A, FER1L3, FLJ14466, FLNA, FN1, FN1, GANAB, GDF15, GEM, GNPDA1, GPAA1, GPC6, GPNMB, GPNMB, GUSB, H2AFV, H2AFV, HDAC9, HDLBP, HECW2, HMGA2, HMOX1, HSDL2, HSPBAP1, HSPC196, HYOU1, IDS, IGFBP3, IKBKAP, INSIG1, IPO4, IRS2, JAG1, KDELR3, KIAA0251, KIAA0586, KIAA1211, KIAA1462, KIAA1706, KIAA1754, KRT18, KRT7, KRTAP4-7, LAMP2, LEPR, LEPREL1, LHFPL2, LIF, LOC286044, LOC339229, LOC90693, LRRC8E, MAFG, MAGED2, MCTP1, MGC16291, MGC19764, MGC5618, MRPS30, MRPS31, MTERFD3, MYH9, NAGA, NAV2, NCSTN, NEK9, NEU1, NFKBIZ, NMT2, NPC2, NSUN5C, NTNG1, NUP188, OACT2, OS9, P4HA1, P8, PALM2-AKAP2, PALM2-AKAP2, PARVA, PBX2, PDE4DIP, PDIA4, PDIA6, PEG10, PHF19, PIK4CA, PLEKHM1, PLOD1, PLOD2, PPP1R15A, PPP1R15A, PRKDC, PRSS23, PRSS23, PSEN2, PSMD1, PTPRF, PTPRJ, RAB32, RAB9A, RG9MTD1, RGS4, RHOQ, RND3, RNF25, RNPEP/ //UBE2V1/ //Kua/ //Kua-UEV, RNU17D, ROBO4, RRAGC, RRS1, SEC31L1, SERPINB2, SERPINB7, SESN2, SGEF, SGSH, SKIV2L, SLC25A21, SLC35A3, SLC3A2, SMARCA1, SNAPC1, SNF1LK, SPOCD1, SPTAN1, SQSTM1, ST3GAL6, STC2, STX3A, TFPI2, TFPI2, TGFBI, TGM2, THRAP1, TLN1, TMEM60, TNFAIP3, TRIB3, TRIO, TSC2, UAP1L1, UBAP2L, UPP1, URB, USP11, USP5, VDR, WDR4, YTHDF2, ZCCHC9, ZDHHC20, ZFHX1B, ZNF185, ZNF278, ZNF690, ZNF697 or described gene are to select gene as described below: FN1, ITGAV, LAMA4, LAMB2, LAMC1, LAMB1, LAMB1, LAMA4, LAMA5, LAMC1, LAMA2, LAMB1, LAMA3, SCAMP1, TICAM2, SCAMP1, TICAM2, SCAMP1, SCAMP1, CAMK2B, DL1, ICAM3, CEECAM1, ICAM5, SCAMP1, CAMK1G, CAMSAP1, MCAM, CAMTA1, CKN1, ALCAM, DCAMKL2, CEACAM3, CAMK2D, CAMK2B, SCAMP5, CAMK4, NCAM1, CAMK2G, MYH9, MYH10, MYO1D, MYO5A, MYLK, MYO6, MYO5A, MYO1C, MYLK, MYO6, MYLC2PL, MYO10, MYO6, TPM3, MYO1C, BECN1, MYO1E, TPM3, M-RIP, MYO1B, MYO10, MYO5A, M-RIP, MYO10, MYL6, MYOHD1, BECN1, TPM4, MYLK, MYH10, MYOHD1, LOC221875, LOC402643, MYO15B, LOC129285, MYH11, MYO1B, MYO1C, MYO9B, CDH13, CTNNAL1, CDH13, CDH12, CTNNB1, CDH5, CTNND1, CDH2, CTNNA1, CDH2, PCDHB16, CTNNA1, CELSR2, PCDHB6, PCDHB7, CTNND2, PCDHGC3, PCDHGB4, PCDHGA8, PCDHGA12, PCDHGC5, PCDHGC4, PCDHGB7, PCDHGB6, PCDHGB5, PCDHGB3, PCDHGB2, PCDHGB1, PCDHGA11, PCDHGA10, PCDHGA9, PCDHGA7, PCDHGA6, PCDHGA5, PCDHGA4, PCDHGA3, PCDHGA2, PCDHGA1, CTNND1, CDH23, PCDHB12, PCDHB10, PCDH18, CDH20, PCDH9, PCDHGA12, PCDHGA11, PCDHGA10, PCDHGA6, PCDHGA5, PCDHGA3, PCDH7, CDH18, CDH6, CCBE1, COL10A1, COL12A1, COL13A1, COL18A1, COL1A1, COL21A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL9A1, MMP9, P4HA1, P4HA2, P4HB, PCOLCE, PCOLCE2, PCOTH, PLOD1, PLOD2, PLOD3, CIB1, ILK, ITGA2, ITGA3, ITGA4, ITGA6, ITGAV, ITGB1, ITGB1BP1, ITGB2, ITGB5, ITGBL1, TNC, EMILIN1, ICAM1, HSPG2, HPSE, HS2ST1, SDC2.
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