Synthesis, characterization and biological activity of copper complexes with pyridoxal thiosemicarbazone derivatives. X-ray crystal structure of three dimeric complexes

A dimeric copper complex of the unsubstituted pyridoxal thiosemicarbazone (H2L), [{Cu(HL)(OH2)}(2)]Cl-2.2H(2)O, previously tested on Friend murine cell lines has been recently resynthesized to evaluate its behavior on different murine and human leukemic cell lines and has been compared, in vitro and in vivo, with its monomeric counterpart [Cu(H2L)(OH2)Cl]Cl. On TS/A murine adenocarcinoma cell line in vitro, both compounds significantly inhibit cell proliferation at micromolar concentrations, although the dimeric compound is more active. Despite this cytotoxicity they lack in vivo activity on TLX5 lymphoma. The unsubstituted dimeric [{Cu(HL)(OH2)}(2)]Cl-2.2H(2)O induces apoptosis on CEM and U937 human cell lines, with IC50 concentrations of 1.2 x 10(-5) and 6.7 x 10(-6) M, respectively, but it is inactive on K562. Moreover, it alters significantly the cell cycle of U937 and CEM lines and decreases the telomerase activity of U937. To verify if other dimeric copper complexes show relevant biological activity new complexes with N-substituted pyridoxal thiosemicarbazones have been synthesized and characterized using spectroscopic techniques. Three of them, namely [Cu(Me-2-HL)Cl](2).6H(2)O (Me-2-H2L=pyridoxal NI,N1-dimethylthiosemicarbazone) (1), [Cu(MeMe-HL)Cl](2)Cl-2.4H(2)O (MeMe-HL=pyridoxal NI,N2-dimethylthiosemicarbazone) (2), [Cu(Et-H2L)Cl](2)Cl-2.2H(2)O (Et-H2L=pyridoxal N1-ethylthiosemicarbazone) (3), were also characterized by X-ray diffractometry. These complexes are dimeric and all three present a square pyramidal coordinative geometry with the ligand showing an SNO tridentate behavior. Their biological activities have been tested in vitro on U937, CEM and K562 cell lines to ascertain their effectiveness in comparison to the corresponding unsubstituted complex [(Cu(HL)(OH2)}(2)]Cl-2.2H(2)O. Compound I shows weak proliferation inhibition on all three cell lines, but it does not induce apoptosis and it does not inhibit telomerase activity, compound 2 is not effective at low concentration and is toxic at higher doses; compound 3 inhibits CEM cell growth better than complex I but it does not exert any other biological effect. (C) 2003 Elsevier Inc. All rights reserved.