雄甾-3β,5α,6β-三醇衍生物的合成与抗癌活性
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摘要
目的:合成3β,5α,6β-三羟基雄甾-17β-衍生物并考察其体外抗癌活性,探讨17β-侧链对抗癌活性的影响。方法:以孕烯醇酮为原料经乙酰化、溴仿反应、甲酯化、过氧化氢氧化、水解、再分别进行乙酯化和丁酯化等步骤合成了4个目标化合物;以孕烯醇酮、醋酸去氢表雄酮和薯蓣皂素为原料经过氧化氢氧化等步骤合成了3个目标化合物;3β,5α,6β-三羟基孕甾-20-酮经格式反应等步骤合成2个目标化合物。采用MTT活细胞染色法,对目标化合物进行BEL-7402人肝癌细胞体外增殖抑制实验。结果:合成了9个目标化合物并经元素分析、IR和~1HNMR确证了结构。结论:L7,L11和L12对BEL-7402人肝癌细胞有一定的抗癌活性,L12抗癌活性最好。
Objective: To synthesize androst-3β,5α,6β-triol-17β-derivatives and investigate their anticancer activities and impact of their 17β-side chain on the activities. Methods: Four target compounds were synthesized from pregnenolone as raw material via acetylation,bromoform reaction,methyl esterification,hydrogen peroxide oxidation,hydrolysis,and then ethylesterification and butyl esterification,respectively; 3 target compounds from pregnenolone,prasterone acetate and diosgenin via hydrogen peroxide oxidation etc.; and other 2 target compounds from 3β,5α,6β-trihydroxypregn-20-one via Grignard reaction etc. The proliferation-inhibiting activities of the 9target compounds were tested in human hepatocellular carcinoma BEL-7402 cell line by MTT live cell staining.Results: The 9 compounds were synthesized and corroborated structurally via elemental analysis,IR and~1 HNMR.Conclusion: L7,L11 and L12 have certain anticancer activities,and L12 is the best.
Objective: To synthesize androst-3β,5α,6β-triol-17β-derivatives and investigate their anticancer activities and impact of their 17β-side chain on the activities. Methods: Four target compounds were synthesized from pregnenolone as raw material via acetylation,bromoform reaction,methyl esterification,hydrogen peroxide oxidation,hydrolysis,and then ethylesterification and butyl esterification,respectively; 3 target compounds from pregnenolone,prasterone acetate and diosgenin via hydrogen peroxide oxidation etc.; and other 2 target compounds from 3β,5α,6β-trihydroxypregn-20-one via Grignard reaction etc. The proliferation-inhibiting activities of the 9target compounds were tested in human hepatocellular carcinoma BEL-7402 cell line by MTT live cell staining.Results: The 9 compounds were synthesized and corroborated structurally via elemental analysis,IR and~1 HNMR.Conclusion: L7,L11 and L12 have certain anticancer activities,and L12 is the best.
引文
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[2]WANG P,TANG H,LIU BS,et al.Tumor cell growth inhibitory activity and structure-activity relationship of polyoxygenated steroids from the gorgonian Menella kanisa[J].Steroids,2013,78(9):951-958.
[3]LIU TF,LU XIN,TANG H,et al.3β,5α,6β-Oxygenated sterols from the South China Sea gorgonian Muriceopsis flavida and their tumor cell growth inhibitory activity and apoptosis-inducingfunction[J].Steroids,2013,78(1):108-114.
[4]谢珊珊,朱文博,颜敏,等.3β,5α,6β-三羟基胆甾烷诱导恶性胶质瘤细胞的凋亡[J].中国病理生理杂志,2013,29(4):647-653.
[5]LIN CY,HUO C,KUO LK,et al.Cholestane-3β,5α,6β-triol suppresses proliferation,migration and invasion of human prostate cancer cells[J].PLo S One,2013,8(6):65734.
[6]刘跃金,容士宏.羟基胆烷酸类衍生物的活性研究II.3β,5α,6β-三羟基胆甾烷-24-酸及3β,6β-二羟基胆甾-4-烯-24-酸衍生物的合成及其抗癌活性[J].中国药物化杂志,2004,14(6):344-349.
[7]刘跃金,耿晓宇,王晶明,等.羟基胆烷酸类和羟基胆甾烷类化合物的体内抗癌活性[J].中国现代应用药学,2008,25(7):601-604.
[8]CARVALHO JFS,SILVA MMC,MOREIRA JN,et al.Selective cytotoxicity of oxysterols through structural modulation on rings A and B.synthesis,in vitro evaluation,and SAR[J].J Med Chem,2011,54(18):6375-6393.
[9]MIESCHER K,KAGI H.Preparation of progesterone and neoprogesterone from dehydroandrosterone[J].Helv Chim Acta,1939,22(1):184-195.
[10]KING LC.Preparation of 21-pyridinium-3β-hydroxy-5-pregnene-20-one halides and 3β-hydroxy-5-androstene-17-carboxylic acid[J].J Am Chem Soc,2002,66(9):1612.
[11]RASMUSSON GH,REYNOLDS GF,UTNE T,et al.Azasteroids as inhibitors of rat prostatic 5α-reductase[J].J Med Chem,1984,27(12):1690-1701.
[12]MANCERA O,ROSENKRANZ G,DJERASSI C.Steroids.XIV.1 studies in the 3,6-dihydroxypregnane series(Part 1)[J].J Org Chem,1951,16(2):192-198.
[13]AMENDOLLA C,ROSENKRANZ G,SONDHEIMER F.Steroids.LII.synthesis of steroidal hormone analogs hydroxylated at C6[J].J Chem Soc,1954,9(APR):1226-1233.
[14]RIVERA DG,LEON F,COLL F,et al.Novel 5β-hydroxyspirostan-6-ones ecdysteroid antagonists:synthesis and biological testing[J].Steroids,2006,71(1):1-11.
[15]SHENG R,CHEN Y,GEE HY,et al.Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins[J].Nat Commun,2012,3(4):1249.