Novel 5,7-disubstituted 6-amino-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity

被引：27

作者：

Dubinina, G. G. ^{[1
]}

Platonov, M. O. ^{[1
]}

Golovach, S. M. ^{[1
]}

Borysko, P. O. ^{[1
]}

Tolmachov, A. O. ^{[1
]}

Volovenko, Y. M. ^{[1
]}

机构：

[1] Kiev Natl Univ, ChemBio Ctr, UA-02090 Kiev, Ukraine

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 41卷 / 06期

关键词：

antiproliferative agents; cytostatic agents; pyrrolo[2,3-b]pyrazine; kinase inhibitor; molecular modeling; docking;

D O I：

10.1016/j.ejmech.2006.03.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New derivatives of pyrrolo[2,3-b]pyrazine were synthesized and tested on a panel of cultured human tumor cell lines. It was found that 6-amino-5-(3-chlorophenylamino)-7-(1-methyl-1H-benzo[dlimidazol-2-yl]-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitrile (4j) exhibited a significant antiproliferative activity: GI50 for cell lines RXF 393 (renal cancer) and BT-549 (breast cancer) were 14 and 82 nM, respectively. To identify possible molecular targets, docking of the most active compounds into the active sites of cyclin-dependent kinases was performed. Molecular modeling of the inhibitor-enzyme complexes showed the differences in the binding poses of new pyrrolo[2,3-b]pyrazine derivatives in the kinase ATP-binding site compared with known pyrrolo[2,3-b]pyrazine inhibitors called aloisines. The patterns of drug kinase interactions correlated well with antiproliferative activities of novel derivatives. Key interactions and binding mode of docked compounds are discussed. (c) 2006 Elsevier SAS. All rights reserved.

引用

页码：727 / 737

页数：11