CN101659694B - Anti-tumor cyclic pentapeptide compound and preparation method thereof - Google Patents
Anti-tumor cyclic pentapeptide compound and preparation method thereof Download PDFInfo
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Abstract
本发明公开了一类抗肿瘤环五肽化合物，该抗肿瘤环五肽化合物由五个氨基酸彼此之间以肽键连接成环状构成，所述五个氨基酸选自N-取代氨基酸、芳香基氨基酸、脂肪氨基酸和官能团取代的脂肪氨基酸，且五个氨基酸相互独立，并非完全相同，按随机顺序排列。本发明所述的环五肽化合物具有抗肿瘤活性，特别是针对结肠癌细胞株HT-29、结肠癌细胞株HCT-15、结肠癌细胞株HCT-116、白血病细胞株K562，肺癌细胞株A549、前列腺癌细胞株PC-3、乳腺癌细胞株MDA-MB231、黑色素癌细胞株WM-115以及两种胰腺癌细胞株S2-013和AsPC-1更为突出。The invention discloses a class of anti-tumor cyclic pentapeptide compound. The anti-tumor cyclic pentapeptide compound is composed of five amino acids connected to each other by peptide bonds to form a ring. The five amino acids are selected from N-substituted amino acids, aromatic groups Amino acids, aliphatic amino acids and fatty amino acids substituted by functional groups, and the five amino acids are independent of each other and not identical, arranged in random order. The cyclic pentapeptide compound of the present invention has anti-tumor activity, especially for colon cancer cell line HT-29, colon cancer cell line HCT-15, colon cancer cell line HCT-116, leukemia cell line K562, lung cancer cell line A549 , prostate cancer cell line PC-3, breast cancer cell line MDA-MB231, melanoma cancer cell line WM-115, and two pancreatic cancer cell lines S2-013 and AsPC-1 were more prominent.
Description
Technical field
The present invention relates to one type of peptides with medical active, particularly one type has cyclic pentapeptide compound of anti-tumor activity and preparation method thereof.
Background technology
Cyclic peptide is the more special peptides of a class formation, and proportionately the characteristics of ring are divided into two big types of cyclic peptide and heterocycle peptides.These compounds have good physiology and pharmacologically active mostly, wherein at anti-tumor aspect, show particularly outstandingly.The capromycin of clinical application and ciclosporin are the cyclic peptide medicines that fermentation obtains, and some antitumor cyclic peptide such as Cilengitide have got into the clinical second phase.Similar with the chain peptide, the difference of the order of arranging along with amino acid, the structure of cyclic peptide is different, different in kind, activity is also different.
Owing in the cyclic peptide structures, do not have definite carbon teminal and nitrogen end, be difficult for degraded in vivo, the long transformation period is arranged, show good enzyme stability, be a kind of new important channel of finding new drug at present so research has the medical active cyclic peptide compounds.
Summary of the invention
The purpose of this invention is to provide one type of anti-tumor cyclic pentapeptide compound.
Another object of the present invention provides the preparation method of this anti-tumor cyclic pentapeptide compound.
Anti-tumor cyclic pentapeptide compound of the present invention connects into ring texture with peptide bond each other by five amino acid, and said five amino acid is selected from N-substituted amino acid, aryl amino acid, fatty group amino acid, replaces fatty group amino acid; And five amino acid is separate, is not identical, arranges by random sequence.
Anti-tumor cyclic pentapeptide compound of the present invention in the said five amino acid, at most only contains a N-alkylation amino acid, at least one aryl amino acid, and other are substituted fatty group amino acid of fatty group amino acid or functional group or cyclic amino acid.One in the said five amino acid can be D-type amino acid.
Wherein, the substituting group of said N-substituted amino acid includes but not limited to hydrogen, methyl, ethyl, benzyl, hydroxyl.
Said aryl amino acid comprises substituted aryl amino acid,
Said aryl is selected from aromatic heterocyclics such as phenyl, xenyl, naphthyl, pyridyl, quinolyl, thienyl, pyrryl, furyl, thiazolyl, imidazolyl, pyrazolyl 、 oxazolyl, indyl or benzofuryl;
The amino acid whose substituting group of said substituted aryl is selected from halogen, alkyl, amino, alkylsulfonyl, hydroxyl, alkoxyl group, glycosyl, phenoxy, dimethylamino oxyethyl group, diethylamino ethoxy, dimethylamino propoxy-or diethylin propoxy-, and wherein said alkyl is selected from alkyl, naphthenic base, glycosyl, dimethylaminoethyl, diethyllaminoethyl, pyrryl ethyl or the piperidyl ethyl below 6 carbon;
The substituted fatty group amino acid of said fatty group amino acid or functional group is selected from natural amino acid or D-type alpha-non-natural amino acids such as leucine, Isoleucine, Xie Ansuan, L-Ala, aspartic acid, l-asparagine, L-glutamic acid, l-arginine, Methionin, glycocoll, Serine or Threonine;
Said cyclic amino acid is selected from proline(Pro), oxyproline one.
As of the present invention preferred, the aryl in the said aryl amino acid is 4-alkoxyl phenyl or 4-halogenophenyl; Alkyl in the said 4-alkoxyl group is selected from fatty group and the glycosyl that does not contain the fatty group of functional group below 6 carbon or contain functional group; Halogeno-group in the said 4-halogenophenyl is selected from fluorine, chlorine, bromine or iodine.
Anti-tumor cyclic pentapeptide compound of the present invention has formula (I) structure,
Wherein:
Ar is aryl or substituted aryl,
Aryl comprises aromatic heterocyclics such as phenyl, xenyl, naphthyl, pyridyl, quinolyl, thienyl, pyrryl, furyl, thiazolyl, imidazolyl, pyrazolyl 、 oxazolyl, indyl or benzofuryl;
Substituting group in the substituted aryl comprises halogen, alkyl, amino, alkylsulfonyl, hydroxyl, alkoxyl group, glycosyl, phenoxy, dimethylamino oxyethyl group, diethylamino ethoxy, dimethylamino propoxy-or diethylin propoxy-etc.;
R
1～R
4Respectively do for oneself independently sec.-propyl, isobutyl-, methyl, aminoalkyl group, guanidine alkylation, carboxyalkyl, carboxamide alkyl, ethyloic or hydroxyalkyl etc.;
R`
1～R`
5Respectively do for oneself independent hydrogen, methyl or ethyl etc.
Further; The cyclic pentapeptide compound of formula (I) structure; Said Ar is the 4-alkoxy benzene, and wherein the alkyl in the 4-alkoxy benzene is methyl, ethyl, propyl group, sec.-propyl, butyl, phenyl, benzyl, glycosyl, dimethylaminoethyl, diethyllaminoethyl, dimethylamino-propyl, diethylin propyl group, (1-pyrryl) ethyl or (piperidino) ethyl etc.
Anti-tumor cyclic pentapeptide compound of the present invention demonstrates good activity to kinds of tumor cells.
The preparation of anti-tumor cyclic pentapeptide compound according to the invention adopts liquid-phase synthesis process to realize; Its strategy is the technology of Boc protection amino acid nitrogen end; Synthetic route is the convergence type of 2+3; The growth of peptide chain uses HBTU or HATU or HCTU or PyBOP etc. as condensing agent, and its compound method comprises the steps:
(1) tripeptide fragment is synthetic:
(2) dipeptides is segmental synthetic:
(3) the synthetic and ring-closure reaction of pentapeptide:
Beneficial effect of the present invention:
Anti-tumor cyclic pentapeptide compound of the present invention has anti-tumor activity; Particularly to colon cancer cell line HT-29, colon cancer cell line HCT-15, colon cancer cell line HCT-116, leukemia cell line K562, lung cancer cell line A549, prostate cancer cell strain PC-3, breast carcinoma cell strain MDA-MB231, malignant melanoma cell strain WM-115 and two kinds of pancreas cancer cell strain S2-013 and AsPC-1 are more outstanding.
Embodiment
Below in conjunction with embodiment the present invention is done further explain.
Synthesizing of 1 pair of fluorobenzene third of instance-bright-bright-figured silk fabrics-bright ring pentapeptide
1) bright-synthesizing to fluorobenzene third methyl esters.2mmol Boc-leucine, 2mmol HBTU, 4mmol DIPEA are joined stirring reaction 30min. in the 100mL single port bottle of being furnished with calcium chloride tube that fills 30mL THF and 4mL DMF solution; And then adding 1mmol P-fluoropnenylalanine methyl esters, stirring reaction spends the night under room temperature.Reaction solution concentrates removes most of solvent, resistates with acetic acid ethyl dissolution after, respectively wash 2 times with 20mL water, 20mL 5%NaHCO3, the saturated NaCl of 20mL respectively, organic phase is with anhydrous Na 2SO4 dried overnight.Filter, concentrate, recrystallization gets the off-white color solid product, and productive rate is 92%.Then this is dissolved in 30mL methylene dichloride and the 20mL trifluoracetic acid stirring reaction 45min under room temperature.The decompression remove DCM and TFA, promptly get product bright-to the thick product of fluorobenzene third methyl esters.
2) Boc-bright-bright-figured silk fabrics tripeptides synthetic.In filling the 100mL single port bottle of 30mL THF, 4mL DMF, 2mmol Boc-leucine and 2mmol HBTU and 4mmol DIPEA, under agitation condition, add the valine methyl ester hydrochloride of 1mmol, room temperature reaction spends the night.Reaction solution concentrates, and in the gained resistates, adds 50mL water, with 40mL ethyl acetate extraction 5 times, merges organic phase, and water, 5%NaHCO3,2%HCl, saturated NaCl respectively wash 2 times respectively, and anhydrous Na 2SO4 is dry, filters, and is concentrated.In residuum, add 30mL DCM and 20mL TFA, stirring reaction 45min under the room temperature.DCM and TFA are removed in decompression, obtain bright-figured silk fabrics methyl esters trifluoroacetate.This salt is dissolved in 30mL THF and 4mL DMF, after this adds the DIPEA of 2mmol Boc-leucine and 2mmol HBTU and 4mmol, stirred overnight.Reaction solution concentrates, and in the gained resistates, adds 50mL water, uses ethyl acetate extraction, and organic phase water, 5%NaHCO3, the saturated NaCl of 2%HCl is respectively respectively washed anhydrous Na 2SO4 dried overnight 2 times.Filter, concentrate, product gets solid product, productive rate 83% through recrystallization purifying.With 17.5mL THF dissolving gained solid, and transfer in the flask of the solution that fills 5mmol LiOH and the formation of 2.5mL water stirring reaction 6h under the room temperature.THF is removed in decompression, adds 20mL water, with the pH to 4.5-6 of 2% hydrochloric acid conditioning solution, uses ethyl acetate extraction, merges organic phase, anhydrous Na 2SO4 dried overnight.Filter, concentrate, promptly get Boc-bright-bright-figured silk fabrics tripeptides.
3) synthesizing fluorobenzene third-bright-bright-figured silk fabrics-bright pentapeptide.Fill 1.1mmol Boc-bright-the 30mL THF and 6mL DMF solution of bright-figured silk fabrics tripeptides in; The DIPEA that adds 2.5mmol HATU and 5mmol earlier; Stirring and dissolving continued reaction 10min; Add again 1mmol bright-to fluorobenzene third methyl esters, stirring reaction spends the night under room temperature condition, with the progress of TLC detection reaction.Concentrating under reduced pressure adds water 150mL, with ethyl acetate extraction five times, merges organic phase.Water, 5%NaHCO successively
3, 2% hydrochloric acid and saturated aqueous common salt respectively wash twice, anhydrous sodium sulfate drying.Suction filtration, removal of solvent under reduced pressure, recrystallization gets Boc-bright-bright-figured silk fabrics-bright-to fluorobenzene third methyl esters, productive rate 88%.With 30mL THF dissolving gained solid, and transfer in the flask of the solution that fills 5mmol LiOH and the formation of 4mL water stirring reaction 8h under the room temperature.Follow the tracks of reaction with TLC, question response finishes the back decompression and removes THF.In resistates, add water 30mL, transfer pH=3～4 with Hydrogen chloride, 80mL ethyl acetate extraction four times merges organic phase, and anhydrous sodium sulfate drying spends the night.Concentrating under reduced pressure obtains Boc-bright-bright-figured silk fabrics-bright-to behind fluorobenzene third pentapeptide, be dissolved in the solution of 30mL methylene dichloride and 30mL trifluoroacetic acid, stirring at normal temperature is reacted 2h.Methylene dichloride and trifluoroacetic acid are removed in decompression, promptly get fluorobenzene third-bright-bright-figured silk fabrics-bright pentapeptide.
4) to the synthetic 0.5mmol of fluorobenzene third-bright-bright-figured silk fabrics-bright ring pentapeptide to fluorobenzene third-bright-bright-figured silk fabrics-bright joining in the single port bottle, be dissolved in the solution that 30mL DMF and 270mL methylene dichloride form.After the stirring and dissolving, add 2.5mmol PyBOP, 0.5mmol HATU, 6mmol diisopropylethylamine, stirring at normal temperature reaction 36h.Concentrating under reduced pressure removes and to desolvate, and in residual solution, adds 50mL water, with 100mL ethyl acetate extraction five times, and the merging organic phase.Water, 5% NaHCO successively
3, 2% hydrochloric acid, water and saturated aqueous common salt respectively wash twice, anhydrous sodium sulfate drying spends the night.Suction filtration concentrates to remove and desolvates.Through purification by silica gel column chromatography, obtain fluorobenzene third-bright-bright-figured silk fabrics-bright ring pentapeptide, productive rate 64%.1H NMR (500MHz, CDCl3) δ 0.83 (d, J=7.0Hz, 3H), 0.86 (d, J=6.5Hz, 3H), 0.89 (d, J=7.0Hz, 3H), 0.96 (d; J=7.5Hz, 9H), 0.99 (d, J=7.0Hz, 6H), 1.37-1.43 (m, 1H), 1.48-1.50 (m, 2H), 1.56-1.59 (m; 2H), 1.70-1.72 (m, 2H), 1.84-2.01 (m, 2H), 2.36 (m, 1H), 3.08 (dd, J=13.0Hz, 5.5Hz; 1H), 3.22 (t, J=7.5Hz, 1H), 3.66 (brs, 1H), 4.03 (t, J=7.5Hz, 1H), 4.35 (dd; J=10.5Hz, 6Hz, 1H), 4.42 (t, J=8.0Hz, 1H), 4.78 (dd, J=9.0Hz, 3.0Hz, 1H); 6.64 (brs, 1H), 6.84 (brs, 1H), 7.02 (d, J=7Hz, 2H), 7.17 (d, J=7Hz, 2H), 7.48 (brs, 1H), 7.53 (brs, 1H); HRMS (ESI, M+1) C32H50FN5O5, calculated value are 603.3796, measured value is 603.3794.
Synthesizing of instance 2 bright-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol ring pentapeptide
1) bright-4-methoxyl group phenylpropyl alcohol methyl esters is synthetic.2mmol Boc-leucine, 2mmol HBTU, 4mmol DIPEA are joined stirring reaction 30min. in the 100mL single port bottle of being furnished with calcium chloride tube that fills 30mL THF and 4mL DMF solution; And then adding 1mmol 4-anisole alanine methyl ester, stirring reaction spends the night under room temperature.Reaction solution concentrates removes most of solvent, resistates with acetic acid ethyl dissolution after, respectively wash 2 times with 20mL water, 20mL 5%NaHCO3, the saturated NaCl of 20mL respectively, organic phase is with anhydrous Na 2SO4 dried overnight.Filter, concentrate, recrystallization gets the off-white color solid product, and productive rate is 85%.Then this is dissolved in 30mL methylene dichloride and the 20mL trifluoracetic acid stirring reaction 45min under room temperature.The decompression remove DCM and TFA, promptly get product bright-the thick product of 4-methoxyl group phenylpropyl alcohol methyl esters.
2) Boc-bright-bright-figured silk fabrics tripeptides synthetic.In filling the 100mL single port bottle of 30mL THF, 4mL DMF, 2mmolBoc-leucine and 2mmol HBTU and 4mmol DIPEA, under agitation condition, add the valine methyl ester hydrochloride of 1mmol, room temperature reaction spends the night.Reaction solution concentrates, and in the gained resistates, adds 50mL water, with 40mL ethyl acetate extraction 5 times, merges organic phase, and water, 5%NaHCO3,2%HCl, saturated NaCl respectively wash 2 times respectively, and anhydrous Na 2SO4 is dry, filters, and is concentrated.In residuum, add 30mL DCM and 20mL TFA, stirring reaction 45min under the room temperature.DCM and TFA are removed in decompression, obtain bright-figured silk fabrics methyl esters trifluoroacetate.This salt is dissolved in 30mL THF and 4mL DMF, after this adds the DIPEA of 2mmol Boc-leucine and 2mmol HBTU and 4mmol, stirred overnight.Reaction solution concentrates, and in the gained resistates, adds 50mL water, uses ethyl acetate extraction, and organic phase water, 5%NaHCO3,2%HCl and saturated NaCl is respectively respectively washed anhydrous Na 2 times
2SO
4Dried overnight.Filter, concentrate, product gets solid product, productive rate 83% through purification by silica gel column chromatography.With 17.5mL THF dissolving gained solid, and transfer in the flask of the solution that fills 5mmolLiOH and the formation of 2.5mL water stirring reaction 6h under the room temperature.THF is removed in decompression, adds 20mL water, with the pH to 4.5-6 of 2% hydrochloric acid conditioning solution, uses ethyl acetate extraction, merges organic phase, anhydrous Na 2SO4 dried overnight.Filter, concentrate, promptly get Boc-bright-bright-figured silk fabrics tripeptides.
3) bright-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol pentapeptide is synthetic.Fill 1.1mmol Boc-bright-the 30mL THF and 6mL DMF solution of bright-figured silk fabrics tripeptides in; The DIPEA that adds 2.5mmol HATU and 5mmol earlier; Stirring and dissolving continued reaction 10min; Add again 1mmol bright-4-methoxyl group phenylpropyl alcohol methyl esters, stirring reaction spends the night under room temperature condition, with the progress of TLC detection reaction.Concentrating under reduced pressure adds water 150mL, with ethyl acetate extraction five times, merges organic phase.Water, 5%NaHCO3,2% hydrochloric acid and saturated aqueous common salt respectively wash twice, anhydrous sodium sulfate drying successively.Suction filtration, removal of solvent under reduced pressure, recrystallization gets Boc-bright-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol methyl esters pentapeptide, productive rate 88%.With 30mL THF dissolving gained solid, and transfer in the flask of the solution that fills 5mmol LiOH and the formation of 4mL water stirring reaction 8h under the room temperature.Follow the tracks of reaction with TLC, question response finishes the back decompression and removes THF.In resistates, add water 30mL, transfer pH=3～4 with Hydrogen chloride, 80mL ethyl acetate extraction four times merges organic phase, and anhydrous sodium sulfate drying spends the night.Concentrating under reduced pressure is dissolved in the solution of 30mL methylene dichloride and 30mL trifluoroacetic acid after obtaining Boc-dried meat-bright-figured silk fabrics-bright-phenylpropyl alcohol pentapeptide, stirring at normal temperature reaction 2h.Methylene dichloride and trifluoroacetic acid are removed in decompression, promptly get bright-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol pentapeptide.
4) bright-bright-figured silk fabrics-bright-synthesizing to methoxy phenylpropyl alcohol ring pentapeptide.With 0.5mmol bright-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol pentapeptide joins in the single port bottle, is dissolved in the solution that 30mL DMF and 270mL methylene dichloride form.After the stirring and dissolving, add 2.5mmol PyBOP, 0.5mmol HATU, 6mmol diisopropylethylamine, stirring at normal temperature reaction 36h.Concentrating under reduced pressure removes and to desolvate, and in residual solution, adds 50mL water, with 100mL ethyl acetate extraction five times, and the merging organic phase.Water, 5%NaHCO3,2% hydrochloric acid, water and saturated aqueous common salt respectively wash twice successively, and anhydrous sodium sulfate drying spends the night.Suction filtration concentrates to remove and desolvates.Through purification by silica gel column chromatography, obtain bright-bright-figured silk fabrics-bright--4-methoxyl group phenylpropyl alcohol ring pentapeptide, productive rate 67%.1H NMR (500MHz, CDCl3) δ 0.78 (d, J=7.0Hz, 3H), 0.83 (d, J=6.5Hz, 3H), 0.88-0.96 (m, 15H), 0.99 (d; J=7.0Hz, 3H), 1.14 (m, 1H), 1.38-1.41 (m, 2H), 1.43-1.50 (m, 2H), 1.62-1.65 (m, 2H); 1.78-1.90 (m, 2H), 2.02 (m, 1H), 3.38 (m, 1H), 3.46 (m, 1H), 3.66 (brs, 1H); 3.76 (s, 3H), 4.20 (m, 1H), 4.43 (m, 1H), 4.51-4.0 (m, 2H), 4.69 (m 1H); 6.62 (brs, 1H), 6.81 (d, J=10Hz, 2H), 7.14 (d, J=10Hz, 2H), 7.28 (brs, 2H), 7.73 (brs, 1H); HRMS (ESI, M+1) C33H53N5O6, calculated value are 615.3996, measured value is 615.3989.
The experiment of instance 3 anti-tumor activities
Test based on tetrazolium (MTT) method.Testing sample ring pentapeptide is mixed with the DMSO solution of different concns such as 10,5,1,0.5,0.1 μ mol/L respectively.The tumour cell of selecting is suspended in the PRMI nutrient solution of 10% fresh foetal calf serum; Trysinization; And cell counting, with cell concn constant volume to 5 * 104cells/mL, every hole adds 200 μ L cells in 96 orifice plates; The soup 10 μ L that in every hole, add different concns then are at 37 ℃, 100% relative humidity with contain CO
2With AIR Proportional is to cultivate 72h in 5: 95 the incubator of mixed atmosphere.After in every hole, adding the MTT solution of 10 μ L 5mg/mL, then continue to cultivate 4h under these conditions.Add the aqueous isopropanol of 0.04N HCl in each hole, be determined at the 570nm place solution light absorption ratio relevant, measure the cell proliferation situation with viable count with ELIASA.Every group of experiment all has backup, and the report data are its MV.0.0325 bright under the condition of μ mol/mL-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol ring pentapeptide is to colon-cancer cell strain HT-29, colon cancer cell line HCT-15, colon cancer cell line HCT-116, leukemia cell line K562, the inhibiting rate of lung cancer cell line A549, breast carcinoma cell strain MDA-MB231 surpasses 95%.
Obviously, the above embodiment of the present invention only be for clearly the present invention is described and is done for example, and be not to be qualification to embodiment of the present invention.For the those of ordinary skill in affiliated field, on the basis of above-mentioned explanation, can also make other multi-form variation or change.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.
Claims (6)
1. anti-tumor cyclic pentapeptide is characterized in that, this compounds connects into ring texture with peptide bond each other by five amino acid, and said five amino acid is selected from substituted-phenyl L-Ala, fatty group amino acid, and its structure is shown in (I).
Wherein:
Ar is a substituted-phenyl, and substituting group wherein is fluorine, chlorine or methoxyl group;
Be sec.-propyl one of among R1～R4, all the other are isobutyl-.
2. anti-tumor cyclic pentapeptide compound according to claim 1 is characterized in that, only comprises a substituted benzene L-Ala in the structure, and said substituting group is one of in methoxyl group, chlorine, the fluorine.
3. anti-tumor cyclic pentapeptide compound according to claim 1 is characterized in that, said fatty group amino acid is leucine or Xie Ansuan.
4. anti-tumor cyclic pentapeptide compound according to claim 1 is characterized in that said amino acid is the L-configuration.
5. anti-tumor cyclic pentapeptide compound according to claim 1 is characterized in that, said anti-tumor cyclic pentapeptide compound is to fluorobenzene third-bright-bright-figured silk fabrics-bright ring pentapeptide or bright-bright-figured silk fabrics-bright-4-methoxyl group phenylpropyl alcohol ring pentapeptide.
6. the application of the described anti-tumor cyclic pentapeptide compound of claim 1 in the preparation antitumor drug is characterized in that described tumour is intestinal cancer, colorectal carcinoma, white blood disease, lung cancer and mammary cancer.
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| CN1183104A (en) * | 1995-04-28 | 1998-05-27 | 武田药品工业株式会社 | Cyclic pentapeptide LH-RH receptor antagonists |
| WO2000044404A2 (en) * | 1999-02-01 | 2000-08-03 | Childrens Hospital Los Angeles | Methods for inhibiting brain tumor growth by using selected integrin antagonists |
| CN1295578A (en) * | 1998-03-31 | 2001-05-16 | 杜邦药品公司 | Pharmaceuticals for imaging of angiogenic disorders |
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| CN1295578A (en) * | 1998-03-31 | 2001-05-16 | 杜邦药品公司 | Pharmaceuticals for imaging of angiogenic disorders |
| WO2000044404A2 (en) * | 1999-02-01 | 2000-08-03 | Childrens Hospital Los Angeles | Methods for inhibiting brain tumor growth by using selected integrin antagonists |
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