1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy

doi:10.1016/j.ejmech.2019.04.040

	1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy
	Jiang, Junhang 1; Zhang, Hao 2; Wang, Chongqing 1; Zhang, Qingsen 1; Fang, Shaoyu 1; Zhou, Ruolan 1; Hu, Jian 1; Zhu, Ju 1; Zhou, Youjun 1; Luo, Cheng 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2019-09-01
卷号	177 页码:448-456
关键词	Microtubule-targeting agents Colchicine site inhibitors Cis-trans photoisomerization X-ray co-crystal structure Water-soluble prodrug
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2019.04.040
通讯作者	Zhou, Youjun(zhuoyoujun@smmu.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Zheng, Canhui(canhuizheng@smmu.edu.cn)
英文摘要	The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special waterbridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 mu M. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound. (C) 2019 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21572266] ; Shanghai Rising Star Program of China[16QA1404800] ; K. C. Wong Education Foundation ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401]
WOS关键词	TUBULIN POLYMERIZATION ; BINDING ; AGENTS ; MITOSIS ; TARGET ; DRUGS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000474316600031
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289331]
专题	中国科学院上海药物研究所
通讯作者	Zhou, Youjun; Luo, Cheng; Zheng, Canhui
作者单位	1.Second Mil Med Univ, Sch Pharm, 325 Guohe Rd, Shanghai 200433, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Junhang,Zhang, Hao,Wang, Chongqing,et al. 1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,177:448-456.
APA	Jiang, Junhang.,Zhang, Hao.,Wang, Chongqing.,Zhang, Qingsen.,Fang, Shaoyu.,...&Zheng, Canhui.(2019).1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,177,448-456.
MLA	Jiang, Junhang,et al."1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 177(2019):448-456.