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

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• 作者：G.G. Dubinina ; M.O. Platonov ; S.M. Golovach ; P.O. Borysko ; A.O. Tolmachov ; Y.M. Volovenko
• 关键词：Antiproliferative agents ; Cytostatic agents ; Pyrrolo[2 ; 3-b]pyrazine ; Kinase inhibitor ; Molecular modeling ; Docking
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：June 2006
• 年：2006
• 卷：41
• 期：6
• 页码：727-737
• 全文大小：436 K

文摘

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[d]imidazol-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.