Syniugin A. Synthesis of the novel protein kinase CK2 inhibitors, based on 3-substituted quinoline derivatives scaffold

The synthetic small molecular inhibitors of protein kinase CK2 on the basis of on 3-substituted quinoline derivatives. The search of new inhibitors of CK2 using methods of molecular modeling, chemical synthesis and biochemical testing. The molecular docking, biochemical testing, chemical synthesis, LCMS, NMR spectrometry. New synthesis methods of the 2-quinolinone-3-yl propionic acid derivatives, 2,3-dihydro-1H-pyrrolo[2,3-b]quinoline derivatives, 3-(aminomethyl) - and 3-(aminoethyl)quinoline-2-ones from appropriate anilides was developed, using modification of the O. Meth-Cohn method. Five combinatorial series including 110 compounds was synthesized, which have been investigated in biochemical tests in vitro, using radioactively labeled 32P-ATP. Structure-activity relationships (SAR) of the synthesized compounds were studied. The established binding models were used for prediction of the ways for further chemical optimization with the aim to obtain more active inhibitors based on 3-carboxyquinoline derivatives and their amides. As a result of this optimization 42 nanomolar CK2 inhibitors have been developed and can be used in further research to study structure and cellular functions of this protein kinase. The binding models of inhibitors with protein kinase CK2 and SAR can be used for the development of novel highly potent protein kinase inhibitors. The scope-bioorganic chemistry.