Journal
INORGANIC CHEMISTRY
Volume 59, Issue 7, Pages 4924-4935Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.0c00182
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Funding
- National Science Foundation [CHE-1665136, CHE-1800245]
- National Cancer Institute [R25-CA134283]
- National Institutes of Health - NIMHD [U01 HL127518]
- NHGRI
- NHLBI
- NIA
- NIAAA
- NIBIB
- NICHD
- NIDA
- NINDS
- NINR
- NLN
- Department of Energy [DEFG02-08CH11538]
- Kentucky Research Challenge Trust Fund
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A series of hybrid ligands (H2L1-H2L3) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid O-alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper (4-6), nickel (7-9), and zinc (10-12) 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 similar to 160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates 4-12 were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives 4 and 6 were found to have potent and cancer-selective antiproliferative effects, with GI(50) 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 10 was transmetalated in the presence of equimolar copper, whereas nickel complex 7 was not. Copper complexes 4 and 6 were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, 4 and 6 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.
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