Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

作     者：Ruxuan Wang Rentao Zhang Haoran Yang Nina Xue Xiaoguang Chen Xiaoming Yu Ruxuan Wang;Rentao Zhang;Haoran Yang;Nina Xue;Xiaoguang Chen;Xiaoming Yu

作者机构：State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2023年第34卷第2期

页      面：434-439页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the CAMS Innovation Fund for Medical Sciences (Nos. CIFMS 2016-I2M-3–009 and CIFMS 2017I2M-3–011) the National Natural Science Foundation of China (No. 21272279) 

主　　题：Hsp90 inhibitors Geldanamycin derivatives Total synthesis Structure-activity relationship Anticancer 

摘      要：Heat shock protein 90(Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin(GA) is the first identified Hsp90 inhibitor that exhibited potent anticancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1(C6-ethyl) and 2(C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds1 and 2 bind to Hsp90 protein with the IC_(50) of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.