Synthesis, Characterization, and Biological Activity of Hybrid Thiosemicarbazone-Alkylthiocarbamate Metal Complexes.

A series of hybrid ligands (-) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid -alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper (-), nickel (-), and zinc (-) and characterized by spectroscopy, electrochemistry, and single crystal X-ray crystallography. The chelated metals displayed substantial anodic shifts in the Cu reduction potential of ∼160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates - were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives and were found to have potent and cancer-selective antiproliferative effects, with GI values less than 100 nM in A549 lung adenocarcinoma cells compared with at least 20-fold less activity in IMR90 nonmalignant lung fibroblasts. In comparison, the nickel complexes were much less active and had little cancer-selectivity. Varying by ligand, the zinc complexes were less potent or had comparable activity compared to that of the corresponding copper complex. UV-visible spectroscopy indicated that zinc complex was transmetalated in the presence of equimolar copper, whereas nickel complex was not. Copper complexes and were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, and were substantially more active against A549 cancer cells than Cu(ATSM) and were more cancer-selective (for A549 compared to IMR-90) than Cu(GTSM). Our results suggest that hybrid thiosemicarbazone-alkylthiocarbamate copper complexes have potential for development as new anticancer agents.