Synthesis, substitution kinetics and electrochemistry of betadiketonato titanium and titanocene complexes with biomedical applications

[摘要] English: Synthetic routes to prepare 13 new and 11 known complexes of the metals Ti, Zr, Hf and V with one bichelating ligands have been developed and optimised. A variety bi-chelating titanocenyl(IV) complexes of the form [Tc(CH3CXCHCOR)]+ClO4- {Tc = (C5H5)2Ti2+, X = O, S and R = CH3, Ph, CF3, Fc and OCH3} and [Tc(LL')]{LL' = 1,2-benzenediolato, 1,2-benzenedithiolato and 2,2-biphenyldiolato} were synthesised. Similar metallocene complexes, namely [Vc(CH3COCHCOFc)]+ClO4- and [Mc(CH3COCHCOOCH3)]+ClO4 - with Mc = (C5H5)2V2+, (C5H5)2Zr2+ and (C5H5)2Hf2+ were also successfully prepared. A series of 7 new and 4 known bis-β-diketonato metal complexes of the form [M(Cp)(Cl)(CH3COCHCOR)2], where M = Ti, Zr, Hf and V and R = CH3, Ph, CF3 and Fc were also prepared.Electrochemical studies in CH3CN on the mono-β-diketonato titanocenyl(IV) complexes all revealedchemical and electrochemical reversible Ti4+/Ti3+ couples, with the Fc/Fc+ couple of the[Tc(CH3COCHCOFc)]+ClO4- complex electrochemically quasi-reversible. The formal reduction potential of theTi4+/Ti3+ couple increased with an increase in group electronegativity of the R group of the β-diketonato ligand.Electrochemical studies in CH3CN on for the metallocene dichlorides of Zr, Hf and V, all showed chemical irreversibility, Ti showed chemical reversibility but electrochemical irreversibile with Epc dependent on the metals' atomic electronegativity. The M4+/M3+ couple of the bis-acetylacetonato metal(IV) complexes, [M(Cp)(Cl)(CH3COCHCOCH3)2] with M = Ti, Zr, Hf and V all displayed a chemical irreversible character in contrast to the bis-ferrocenylacetone metal(IV) complexes, [M(Cp)(Cl)(CH3COCHCOFc)2] with M = Ti, Zr, Hf and V, showed chemical reversibility, but electrochemical irreversibility for the M4+/M3+ couple. The Fc/Fc+ couples display electrochemical quasi-reversibility except for the V-complex. Substitution kinetics involving substitution of the bidentate ligand from [Tc(OC6H4O)],[Tc(CH3COCHCOCH3)]+ClO4 -, [Tc(CH3CSCHCOCH3)]+ClO4 - and [Tc(OC6H4C6H4O)] with either acetylacetone, thioacetylacetone and 2,2-biphenyldiol showed the following stability series:{most stable} [Tc(OC6H4C6H4O)] (7 membered ring) > [Tc(CH3CSCHCOCH3)]+ (6 membered ring) > [Tc(CH3COCHCOCH3)]+ (6 membered ring) > [Tc(OC6H4O)] (5 membered ring) {least stable}Large negative activation entropy ΔS* found for all substitution reactions, indicated towards an associative mechanism of substitution.Cytotoxic studies revealed that complexes containing more than one antineoplastic moiety,[Tc(CH3COCHCOFc)]+ClO4 -, and [Ti(Cp)(Cl)(CH3COCHCOFc)2], showed better cytotoxicity than TcCl2 (currently in clinical trial phase II) for the CoLo and HeLa cell lines, probably due to a synergistic effect of the ferrocenyl ligand and the titanocenyl moiety.

[发布机构] University of the Free State