Novel chelate complexes of Co(II), Ni(II), Cu(II), Pd(II) derived from anti- and syn-isomers of 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetic acid with pro-/antiproliferative actions on endothelial cells

Abstract Anti - and syn -isomers of 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetic acid ( anti- A and syn- A respectively) were used as potential biologically active polydentate complexing agent for Co 2+ , Ni 2+ , Cu 2+ and Pd 2+ ions for the synthesis of novel complex compounds with directed angiogenesis-correcting action. It shown that the location of functional groups in ligand molecules, the electronic structure of metal as complexing agent and the synthesis conditions affect the localization of coordination bonds and the structure of formed complexes. The interaction of ethanol solutions of metal salts with anti- A and syn- A in an acidic medium at the component ratios M:L = 1:1 and 1:2 leads to the formation of complexes [Co( anti- A)(H 2 O) 3 SO 4 ] ( 1 ); [Ni( anti- A)(H 2 O) 3 SO 4 ] ( 2 ); [Cu( anti- A) 2 Cl 2 ] ( 3 ); [Pd( anti- A) 2 Cl 2 ] ( 4 ); [Cu( syn -A) 2 Cl 2 ] ( 5 ); [Pd( syn -A)Cl 2 ] ( 6 ) with different coordination of ligands. Coordination mode of ligands identified by IR, UV–Vis, XPS and 1 H ( 13 C) NMR spectra. The structures of salt of the anti- A and complexes 1 , 2 , 6 were determined by X-ray diffraction study. Anti- A is coordinated to metal ions in a chelate manner by the nitrogen atom of the hydroxylimino group and the oxygen atom of the deprotonated carboxyl group. In this case, the 2-aminothiazole fragment does not involve in complexation. Syn- A is coordinated to the central metal ion in neutral form through the nitrogen atoms of hydroxyimino group and thiazole ring. All synthesized complex compounds form stable solutions in neutral medium, which makes it possible to use them as potential biologically active substances. Investigation of biological effects for syn- A shows mitogenic and antiapoptotic activity against endotheliocytes, while anti- A causes inhibition of proliferation almost in the entire concentration range. Complex compounds of Cu 2+ and Pd 2+ with anti -A and syn -A ( 3 – 6 ) cause an increase of antiproliferative activity of endothelial cells compared with baseline complexing agents. In this case, the activity of complexes with syn- A is superior to activity of analogues with anti- A. The results of cytotoxicity tests revealed a pronounced cytotoxic action for complexes 3 and 4 , cytotoxic and proapoptotic activity for 6 and cytostatic effect for 5 . For all compounds investigated, a checkpoint from S to G 2 has been established, which may indicate DNA replication disturbance or dysregulation in the endogenous signals of the cell cycle of endotheliocytes.