Comparative study of the antitumoral activity of phosphine-thiosemicarbazone gold(I) complexes obtained by different methodologies

摘要

A series of phosphino-thiosemicarbazone gold(I) dinuclear complexes obtained by two different synthetic procedures have been prepared. All the compounds have been spectroscopically characterized including single crystal X ray diffraction analysis in some of cases. [Au-2(HL1)Cl-2] (1), [Au-2(HL2)(2)]Cl-2 (2) and [Au-2(HL3)(2)]Cl-2 (3) have been prepared by chemical synthesis using a gold(III) salt as precursor; while [Au-2(L-1)(2)] (4), [Au-2(L-2)(2)] center dot 2CH(3)CN (5) and [Au-2(L-3)(2)] (6) have been isolated from an electrochemical synthesis (HLn = 2-[2-(diphenylphosphanyl)-benzylidene]-N-R-thiosemicarbazone; HL1: R = methyl, HL2: R = methoxyphenyl, HL3: R = nitrophenyl). The in vitro cytotoxic activity of these gold(I) complexes was tested against some human tumor cell lines: HeLa 229 (cervical epithelial carcinoma), MCF-7 (ovarian adenocarcinoma), NCI-H460 (non-small-cell lung cancer) and MRC5 (normal human lung fibroblast), and the IC50 values compared with those of cisplatin. The neutral methyl-substituted complexes 1 and 4 and methoxyphenyl 5 displayed significant cytotoxic activities in all investigated cancer cell lines, being 1 and 4 the most effective. The ability of complexes 1 and 4 to induce cell death by apoptosis in Hela 229 was also investigated by fluorescence microscopy using the apoptotic DNA fragmentation as marker. These results indicated that the inhibition of cell proliferation is mainly due to an apoptotic process. In order to obtain more information about the mechanism of action of these metallocompounds, the interactions of complexes 1 and 4 with the thioredoxin reductase (TrxR) enzyme were analyzed. Both complexes exhibited a strong inhibition of the thioredoxin reductase activity.