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

Abstract

A series of hybrid ligands (<b>H</b>_<b>2</b><b>L</b>^<b>1</b>-<b>H</b>_<b>2</b><b>L</b>^<b>3</b>) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid <i>O</i>-alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper (<b>4</b>-<b>6</b>), nickel (<b>7</b>-<b>9</b>), and zinc (<b>10</b>-<b>12</b>) and characterized by spectroscopy, electrochemistry, and single crystal X-ray crystallography. The chelated metals displayed substantial anodic shifts in the Cu^II/I reduction potential of ∼160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates <b>4</b>-<b>12</b> were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives <b>4</b> and <b>6</b> were found to have potent and cancer-selective antiproliferative effects, with GI₅₀ 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 <b>10</b> was transmetalated in the presence of equimolar copper, whereas nickel complex <b>7</b> was not. Copper complexes <b>4</b> and <b>6</b> were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, <b>4</b> and <b>6</b> 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.