17-[3,6-二氧杂-8-N-(取代肉桂酰基)辛二胺]-17-去甲氧基格尔德霉素新颖衍生物的合成  

Synthesis of Novel 17-[3,6-Dioxa-8-N-(substituted cinnamyol)-octanediamino]-17-demethoxygeldanamycin Derivatives

作　　者：吴云飞[1] 李震宇[1] 王贞[1] 徐洪蛟 武兴康[1] 鲁春华[1] 沈月毛[1] 

机构地区：[1]山东大学药学院天然产物化学教育部重点实验室,济南250012

出　　处：《有机化学》2014年第9期1870-1874,共5页Chinese Journal of Organic Chemistry

基　　金：国家基础研究计划(973项目,No.2010CB833802);国家自然科学基金(Nos.81373304,91313303);长江学者和创新团队发展计划(No.IRT13028);国家杰出青年科学基金(No.30325044)资助项目~~

摘　　要：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.Twenty six new 17-[3,6-dioxa-8-N-（substituted cinnamyol）octanediamino]-17-demethoxygeldanamycins were designed, synthesized and evaluated for their cytotoxicities against the growth of human breast cancer cell line MDA-MB-231 and binding affinities to heat shock protein 90 （Hsp90）. Among these derivatives, 17-（3,6-dioxa-8-N-（（E）-3-（3,5-dimethoxy- phenyl）acrylamido）octanediamino）-17-demethoxygeldanamycin （3u）, was identified as the most potent one （IC50= 1.5 μmol/L, Kd= 1.14 μmol/L）. Additionally, influence of substitutions at the cinnamyol group on the bioactivities of this type of Geldanamycin （GA） derivatives was discussed. This study was anticipated to provide reference for the further structure modi- fications of GA for developing antitumor agents.

关 键 词：热休克蛋白90 格尔德霉素 合成 衍生物 抗肿瘤活性 

分 类 号：TQ465[化学工程—制药化工]