17-[5-(取代肉桂酰胺基)戊二胺]-17-去甲氧基格尔德霉素新颖衍生物的合成  

Synthesis and Preliminary Antitumor Activity Evaluation of 17-(5-(Substituted cinnamamido)pentylamino)-17-demethoxygeldanamycin Derivatives as Potent Hsp90 Inhibitors

作　　者：徐洪蛟 李震宇[1] 王贞[1] 郝慧琳 鲁春华[1] 朱敬[1] 沈月毛[1] 

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

出　　处：《有机化学》2015年第10期2125-2134,共10页Chinese Journal of Organic Chemistry

基　　金：国家基础研究计划(937项目;No.2010CB883802);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）是第一个天然产物来源的强效热休克蛋白90（heat shock protein 90,Hsp90）抑制剂,但临床应用受到其肝毒性的限制.前期构效关系研究表明,在GA的C-17位通过一个烷二胺基连接基团,引入保肝基团肉桂酰基可以降低肝毒性.报道以戊二胺为连接基团,26个17-[5-（取代肉桂酰基）戊二胺]-17-去甲氧基GA新颖衍生物的合成和活性评价.活性测试结果表明,所有的化合物都有较强的抗乳腺癌细胞株MDA-MB-231活性,IC50值在0.12-1μmol·L-1之间.其中,3a和3u是抗肿瘤活性最高的化合物,IC50值均为0.12μmol·L-1,优于阳性对照17-N-烯丙基氨基-17-去甲氧基GA（17-AAG）（IC50=0.27μmol·L-1）,并且3u的肝细胞毒性较低.该类衍生物的初步构效关系研究,为GA类Hsp-90抑制剂和抗肿瘤先导化合物的结构优化提供了有参考价值的基础.Geldanamcyin（GA） is the first potent inhibitor of heat shock protein 90（Hsp90） from natural products. However, its clinical application was limited by the unwanted hepatotoxicity. Our previous studies on the structure-activity relationships of GA derivatives indicated that the introduction of hepatoprotective cinnamyol group via an alkyldiamino linker decreased the hepatotoxicity evidently. In this study, using pentyldiamine as the linker, twenty-six 17-（5-（substituted cinnamamido）pentylamino）-17-demethoxygeldanamycins were designed and synthesized as the inhibitors of Hsp90. All the compounds showed potent antitumor activities against human breast cancer cell line MDA-MB-231 with IC50 ranging from 0.12 to 1 μmol·L-1. Particularly, 17-（5-（cinnamamido）pentylamino）-17-demethoxygeldanamycin（3a） and 17-（5-（2,5-methoxycinnamamido）pentylamino）-17-demethoxygeldanamycin（3u） were proved to be the most potent compounds（IC50=0.12μmol·L-1）, more active than the positive control 17-N-allylamino-17-demethoxygeldanamycin（17-AAG）（IC50=0.27 μmol·L-1） and showed lower hepatotoxicity. Additionally, the preliminary structure-activity relationships among these newly synthesized congeners are briefly discussed, which should provide valuable basis for the structure optimization of GA-type Hsp90 inhibitors and antitumor lead compounds.

关 键 词：热休克蛋白90 格尔德霉素 结构优化 抗肿瘤 

分 类 号：O623.626[理学—有机化学] TQ460.1[理学—化学]