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

doi:10.6023/cjoc201502023

Chin. J. Org. Chem. ›› 2015, Vol. 35 ›› Issue (10): 2125-2134.DOI: 10.6023/cjoc201502023 Previous Articles Next Articles

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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

徐洪蛟, 李震宇, 王贞, 郝慧琳, 鲁春华, 朱敬, 沈月毛

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

收稿日期:2015-02-13 修回日期:2015-05-06 发布日期:2015-06-12
通讯作者: 沈月毛 E-mail:yshen@sdu.edu.cn
基金资助:
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)和国家杰出青年科学基金(No. 30325044)资助项目.

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

Xu Hongjiao, Li Zhenyu, Wang Zhen, Hao Huilin, Lu Chunhua, Zhu Jing, Shen Yuemao

Key Laboratory of Chemical Biology Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Shandong 250012

Received:2015-02-13 Revised:2015-05-06 Published:2015-06-12
Supported by:
Project supported by the National Basic Research Program (973 Program, No. 2010CB833802), the National Natural Science Foundation of China (Nos. 81373304, 91313303), the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13028) and the National Science Found for Distinguished Young Scholars of China (No. 30325044).

1. Synthesis and Preliminary Antitumor Activity Evaluation of 17-(5-(Substituted cinnamamido)pentylamino)-17-demethoxygeldan-amycin Derivatives as Potent Hsp90 Inhibitors.PDF(2464KB)

Abstract

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-methoxycinn-amamido)pentylamino)-17-demethoxygeldanamycin (3u) were proved to be the most potent compounds (IC₅₀＝0.12 μmol·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.

Key words: heat shock protein 90 (Hsp90), geldanamycin (GA), structure optimization, antitumor activity

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Xu Hongjiao, Li Zhenyu, Wang Zhen, Hao Huilin, Lu Chunhua, Zhu Jing, Shen Yuemao. Synthesis and Preliminary Antitumor Activity Evaluation of 17-(5-(Substituted cinnamamido)pentylamino)-17-demethoxygeldan-amycin Derivatives as Potent Hsp90 Inhibitors[J]. Chin. J. Org. Chem., 2015, 35(10): 2125-2134.

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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-demethoxygeldan-amycin Derivatives as Potent Hsp90 Inhibitors

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