2-取代-3-氧代齐墩果烷-12-烯-30-酰胺类化合物的合成与抗肿瘤活性研究

目的设计并合成一系列2-取代-3-氧代-齐墩果烷-12-烯-30-酰胺类化合物,以期提高该类化合物对人前列腺癌PC-3细胞生长抑制活性。方法对18β-甘草次酸的A环、11位羰基及30位羧基进行结构改造,设计并合成了20个目标化合物。采用MTT法研究其对PC-3细胞的生长抑制活性。结果与结论合成20个未见文献报道的化合物,结构均经1H-NMR、LC-MS和IR确证,部分结构经13C-NMR确证。合成的化合物对PC-3细胞显示了不同程度的生长抑制活性,明显好于其母体化合物18β-甘草次酸(18β-glycyrrhetinic acid,GA),其中化合物9a的活性最强,GI50值为6.97μmol·L-1。初步构效关系表明:A环引入2-氰基-3-氧代-1-烯的化合物活性最好,2位引入羟亚甲基与2,3位骈合异口恶唑环类化合物活性相当,2位引入氰基的化合物活性较弱;30位羧基与哌啶及哌啶基哌啶成酰胺活性较好,与4-甲基哌嗪、吗啉和哌嗪成酰胺活性较弱。

The synthesis and antiproliferative effects of 2- substituted-3-oxo-olean-12-en-30-oic amide derivatives in human prostate cells

A novel series of 2-substituted-3-oxo-olean-12-en-30-oic acid amide derivatives were designed and synthesized to improve the efficiency against prostate cancer PC-3 cells. Twenty target compounds were ob- tained through modifying the natural product 18fl-glycyrrhetinic acid（ GA）, whose chemical structures were confirmed by the application of MS, IR, ^1H-NMR and 13C-NMR. The antiproliferation effects of the target compounds against PC-3 were evaluated by MTT assays. The majority of these derivatives showed preferable growth inhibition activity against PC-3 cells than GA. Compound 9a displayed promising activity which pos- sessed 13 to 14-fold potency than GA, particularly, which was worthy to investigate further. Structure-activity relationships revealed that the introduction of 2-cyano-3-oxo-l-en in ring A could significantly improve the antitumor activity;the isoxazole and 2-hydroxyl-3-oxo derivatives had similar activities and were better than 2-cyano-3-oxo ones;the amide derivatives were more potent than GA, compounds bearing 4-piperidyl piperi- dine beared the highest antiproliferation activity.