中文摘要：

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.

英文摘要：

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.