Towards a selective cytotoxic agent for prostate cancer: Interaction of zinc complexes of polyhydroxybenzaldehyde thiosemicarbazones with topoisomerase I

Abstract

Four thiosemicarbazones ligands, H3T(1), H3M(2), H3E(3) and H3P(4) have been prepared with good yield by refluxing 2,4-dihydroxybenzaldehyde with N(4)-substituted thiosemicarbazide in ethanol (H3T(1)=2,4-dihydroxybenzaldehyde thiosemicarbazone; H3M(2)=2,4-dihydroxybenzaldehyde 4-methylthiosemicarbazone; H3E(3)=2,4-dihydroxybenzaldehyde 4-ethylthiosemicarbazone and H3P(4)=2,4-dihydroxybenzaldehyde 4-phenylthiosemicarbazone). Reactions of these ligands with zinc acetates in the presence of 2,2′-bipyridine lead to the formation of zinc(II) complexes of formulation [Zn(bpy)L](5–8) (bpy=2,2′-bipyridine; L=doubly deprotonated thiosemicarbazones=HT(5); HM(6); HE(7) and HP(8)). These compounds were characterized and their cytotoxicity and topoisomerase I inhibition activities studied. X-ray diffraction study indicates that complex 8 is five coordinated and the coordination geometry around zinc(II) is trigonal bipyramidal distorted square based pyramid (TBDSBP). The doubly deprotonated thiosemicarbazone acts as a tridentate ONS-donor ligand while 2,2-bipyridne as the NN-donor ligand. Complexes 6, 7 and 8 are more cytotoxic towards PC3 (prostate cancer cell line) than RWPE-1 (prostate normal cell line). The cytotoxicity and topoisomerase I inhibition activities seem to be dependent on the N(4) substituent of the thiosemicarbazone moiety.