A series of metal complexes based on hybrid ligands derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid O-alkyl esters were synthesized and evaluated for anti-proliferation activity as anti-cancer candidates. The copper, nickel, and zinc complexes were prepared and characterized by spectroscopic, electrochemical, and single crystal X-ray crystallographic methods. The hybrid complexes are easier to reduce as compared to their parent bisthiosemicarbazone derivatives. The metal chelates were evaluated for antiproliferation activity by MTT, clonogenic and trypan blue assays. The copper derivatives were found to be the most potent amongst all synthesized metal chelates. They showed cancer selective antiproliferation activity with GI<sub>50</sub> values less than 100 mM in A549 lung adenocarcinoma cells compared with at least 20-fold less activity in IMR90 non-malignant lung fibroblasts. In comparison, the nickel derivatives were less active and had little cancer-selectivity. The zinc complexes on the other hand were generally less potent although they displayed some activity that may be due to transmetalation with copper from the cellular media. Copper complexes were also assessed in the NCI60 screen and found to have cytotoxic activity towards most solid tumor cell lines. In MTT assays, the copper complexes 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 the hybrid thiosemicarbazone-alkylthiocarbamate copper complexes have potential for development as new anticancer agents.

Synthesis, characterization and biological activity of hybrid thiosemicarbazone-alkylthiocarbamate metal complexes

ACS Fall 2021

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