New metal complexes of NNO tridentate ligands: Effect of metal center and co-ligand on biological activity

In the search for new agents against Ttypanosoma cruzi and cancer the effect of the nature of the metal center and of the presence of a polypiridyl coligand on the antitrypanosomal and antitumoral activities of selected N,N,O ligands [2-(benzothiazol-2-yl hydrazonomethyl phenol (HL1) and 2-(benzothiazol-2-yl-hydrazonomethyl)-6-methoxyphenol (HL2)] is explored. The new complexes [(VO2)-O-V(L1)I, [(VO2)-O-V(L2)], [(VO)-O-IV(L1-H)(phen))] and [Ga-III(L2)(2)](NO3) were synthesized and characterized by using different techniques. The stability of the vanadium complexes in solution was investigated by EPR and V-51 NMR spectroscopies and that of the gallium compound by UV-Vis spectroscopy, H-1 NMR and conductivity measurements. While the vanadium complexes show high stability in DMSO, the gallium complex shows very good stability in DMSO and moderate stability in aqueous - DMSO medium. The cytotoxicity on human tumor cell lines (ovarian A2780, breast MCF7 and prostate PC3 cell lines) that show different sensitivity to cisplatin was evaluated. All the compounds evidenced antiproliferative activity in the micromolar range. The highest cytotoxic activity, in molar units, is shown by [Ga-III(L2)(2)](-NO3) (IC50: 1.7 mu M) and [(VO)-O-IV(L1-H)(phen)] (IC50: 2.7 mu M) against the ovarian cancer cells. With the exception of [(VO2)-O-V(L1)], the cytotoxic activity of the ligands and complexes is similar to that of cisplatin in A2780 cells and surpass cisplatin in the other tumor cells. Regarding the activity on T. cruzi, [(VO)-O-IV(L1-H)(phen)] showed a 10-fold decrease of IC50 with respect to HL1 and an IC50 value (10.7 mu M) in the same order of that of the antitrypanosomal drug Nifurtimox (IC50: 6.0 mu M). HL2 showed significant growth inhibitory effect on the parasite (IC50: 23.5 mu M) and its coordination to Ga(III) lead to a 2-fold increase in activity in molar units (IC50: 14.2 mu M). In order to explain the high inhibitory activity of [(VO)-O-IV(L1-H)(phen)] against the parasite and the tumor cells, the interaction of this compound with plasmid DNA was preliminarily evaluated by AFM. The corresponding images suggest that DNA may be considered as a potential target. (C) 2013 Elsevier B.V. All rights reserved.