Synthesis and biological evaluation of 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4

被引：16

作者：

Liu, Yajing ^{[1
]}

Yang, Di ^{[1
]}

Hong, Zexin ^{[1
]}

Guo, Su ^{[1
]}

Liu, Moyi ^{[1
]}

Zuo, Daiying ^{[2
]}

Ge, Dandan ^{[1
]}

Qin, Mingze ^{[1
]}

Sun, Deyu ^{[3
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China

[2] Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China

[3] Liaoning Canc Hosp & Inst, 44 Xiaoheyan Rd, Dadong Dist, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 146卷

基金：

中国国家自然科学基金;

关键词：

Synthesis; Antiproliferative activity; Crolibulin; Combretastatin A-4; Colchicine binding site inhibitors; THROUGHPUT SCREENING ASSAY; VASCULAR-DISRUPTING AGENTS; COLCHICINE BINDING-SITE; POTENTIAL ANTICANCER AGENTS; TUBULIN POLYMERIZATION; INHIBITORS; DISCOVERY; CELL; 4-ARYL-4H-CHROMENES; DESIGN;

D O I：

10.1016/j.ejmech.2018.01.052

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel 4,6-dipheny1-2-(1H-pyrrol-1-y1)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge to retain the cis-orientations of A-ring and B-ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines. Compounds 6a-d exhibited superior potency, with IC50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：185 / 193

页数：9

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