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

Andres, Sarah A.; Bajaj, Kritika; Vishnosky, Nicholas S.; Peterson, Megan A.; Mashuta, Mark S.; Buchanan, Robert M.; Bates, Paula J.; Grapperhaus, Craig A.

doi:10.1021/acs.inorgchem.0c00182

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

Journal Article · Wed Mar 11 00:00:00 EDT 2020 · Inorganic Chemistry

DOI:https://doi.org/10.1021/acs.inorgchem.0c00182· OSTI ID:1800548

Andres, Sarah A. ^[1];

^[1]; Vishnosky, Nicholas S. ^[1]; Peterson, Megan A. ^[1];

^[1];

^[1]; Bates, Paula J. ^[1];

^[1]

Univ. of Louisville, KY (United States)

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 ~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 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 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). Finally, our results suggest that hybrid thiosemicarbazone–alkylthiocarbamate copper complexes have potential for development as new anticancer agents.

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Research Organization:: Univ. of Louisville, KY (United States)

Sponsoring Organization:: USDOE; National Science Foundation (NSF); National Cancer Institute (NCI); National Institutes of Health (NIH)

Grant/Contract Number:: FG02-08CH11538; CHE-1665136; CHE-1800245; R25-CA134283

OSTI ID:: 1800548

Journal Information:: Inorganic Chemistry, Vol. 59, Issue 7; ISSN 0020-1669

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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CCDC 1912249: Experimental Crystal Structure Determination A., Andres, Sarah; Kritika, Bajaj,; S., Vishnosky, Nicholas https://doi.org/10.5517/ccdc.csd.cc225vgl The current record is supplemented by this dataset	dataset	January 2020
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CCDC 1912252: Experimental Crystal Structure Determination A., Andres, Sarah; Kritika, Bajaj,; S., Vishnosky, Nicholas https://doi.org/10.5517/ccdc.csd.cc225vkp The current record is supplemented by this dataset	dataset	January 2020

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

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