title: Novel 5,7-disubstituted 6-amino-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity.
abstract: 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.
authors: ChemBio Center, Kiev National University, 6 Sosury Street, 02090 Kiev, Ukraine. g.dubinina@univ.kiev.ua
authors: G G
authors: GG
authors: Dubinina
authors: M O
authors: MO
authors: Platonov
authors: S M
authors: SM
authors: Golovach
authors: P O
authors: PO
authors: Borysko
authors: A O
authors: AO
authors: Tolmachov
authors: Y M
authors: YM
authors: Volovenko