Synthesis and in-vitro biological activity of macrocyclic urea Chk1 inhibitors

被引：12

作者：

Li, Gaoquan ^{[1
]}

Tao, Zhi-Fu ^{[1
]}

Tong, Yunsong ^{[1
]}

Przytulinska, Magdalena K. ^{[1
]}

Kovar, Peter ^{[1
]}

Merta, Philip ^{[1
]}

Chen, Zehan ^{[1
]}

Zhang, Haiying ^{[1
]}

Sowin, Thomas ^{[1
]}

Rosenberg, Saul H. ^{[1
]}

Lin, Nan-Horng ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Canc Res, Abbott Pk, IL 60064 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 23期

关键词：

macrocyclic urea; Chk1; inhibitor;

D O I：

10.1016/j.bmcl.2007.09.088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A variety of macrocyclic urea compounds were prepared as potent Chk1 inhibitors by modifying the C5 position of the benzene ring of the macrocyclic urea with ether moieties, aliphatic carbon chains, amide and halides. Enzymatic activity less than 20 nM was observed in 29 of 40 compounds. Compounds 14, 46d, and 48j provided the best overall results in the cellular assays as they abrogated doxorubicin-induced cell cycle arrest (IC50 = 3.31, 3.08, and 3.13 mu M) and enhanced doxorubicin cytotoxicity (IC50 = 0.54, 1.27, and 0.96 mu M) while displaying no single agent activity, respectively. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：6499 / 6504

页数：6

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