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格尔德霉素(geldanamycin,GA)是一个以热休克蛋白90(Hsp90)为靶点的高效抗肿瘤先导物,但其临床应用受到了肝脏毒性的限制.目前通常对其C-17位进行修饰,以保留活性和降低肝毒性.本研究提出了一种GA结构修饰的新思路,即在GA的C-17位引入烷胺基链,进而接入保肝基团肉桂酰基.报道了26个17-(3,6-二氧杂-8-N-(取代肉桂酰基)辛二胺)-17-去甲氧基GA新颖衍生物的合成;体外人乳腺癌细胞株MDA-MB-231生长抑制实验和靶点亲和实验结果表明,化合物3u有明显细胞毒性和靶点选择性(IC50=1.5μmol/L,Kd=1.14μmol/L);并对该类衍生物的构效关系进行了讨论,对深入开展GA结构修饰的相关研究有参考价值.
Geldanamycin (GA) is a highly potent antitumor leader targeted by heat shock protein 90 (Hsp90), but its clinical use is limited by hepatotoxicity, and its C-17 position Modified to preserve the activity and reduce liver toxicity.This study proposed a new idea GA structure modification, that is, the introduction of alkylamino chain at the C-17 position of GA, and then access the hepato group cinnamoyl group reported 26 Synthesis of novel derivatives of 17- (3,6-dioxa-8-N- (substituted cinnamoyl) octanediamine) -17- demethoxy GA; in vitro human breast cancer cell line MDA-MB-231 The results of growth inhibition test and target affinity test showed that compound 3u had obvious cytotoxicity and target selectivity (IC50 = 1.5μmol / L, Kd = 1.14μmol / L). The structure-activity relationship of these derivatives The discussion of the GA structure modification in-depth study of relevant reference value.