Li Zhenyu, Jia Lejiao, Xu Hongjiao, Lu Chunhua, Shena Yuemao
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, Shandong, P. R. China.
Med Chem. 2015;11(5):482-8. doi: 10.2174/1573406411666141230104953.
A series of 17-phenylpropylamine/phenoxyethylamine-substituted derivatives of geldanamycin (GA) was synthesized and evaluated for the anti-proliferation activity on human cancer cell line MDA-MB-231. All the derivatives exhibited potent cytotoxicity with IC50 values range from 0.35 to 1.03 µM. Among them, 17-(2-phenoxyethylamino)-17-demethoxygeldanamycin (3) was identified as the most potent compound. Hepatotoxicity test in mice demonstrated that the levels of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 3-treated group were lower than that of GA-treated group, indicating that compound 3 was a promising antitumor candidate. Additionally, the Hsp90 inhibitory activity of compound 3 was more active than 17-AAG. Docking and molecular dynamics (MD) refinements of this new series of GA derivatives were also investigated, suggesting a theoretical model between 17- phenylpropylamine/phenoxyethyl-amines and Hsp90.
合成了一系列格尔德霉素（GA）的17-苯丙胺/苯氧乙胺取代衍生物，并评估了它们对人癌细胞系MDA-MB-231的抗增殖活性。所有衍生物均表现出强大的细胞毒性，IC50值范围为0.35至1.03μM。其中，17-（2-苯氧乙氨基）-17-去甲氧基格尔德霉素（3）被确定为最有效的化合物。小鼠肝毒性试验表明，3处理组的天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平均低于GA处理组，表明化合物3是一种有前景的抗肿瘤候选物。此外，化合物3的Hsp90抑制活性比17-AAG更活跃。还研究了这一系列新的GA衍生物的对接和分子动力学（MD）优化，提出了17-苯丙胺/苯氧乙胺与Hsp90之间的理论模型。
