Ligand and Linkage Isomers of Bis(ethylthiocarbamato) Copper Complexes with Cyclic CH Backbone Substituents: Synthesis, Characterization, and Antiproliferation Activity.

A series of isomeric bis(alkylthiocarbamate) copper complexes have been synthesized, characterized, and evaluated for antiproliferation activity. The complexes were derived from ligand isomers with 3-methylpentyl (HL) and cyclohexyl (HL) backbone substituents, which each yield a pair of linkage isomers. The thermodynamic products CuL have two imino N and two S donors resulting in three five-member chelate rings (555 isomers). The kinetic isomers CuL have one imino and one hydrazino N donor and two S donors resulting in four-, six-, and five-member rings (465 isomers). The 555 isomers have more accessible Cu potentials (E = -811/-768 mV vs. ferrocenium/ferrocene) and lower energy charge transfer bands than their 465 counterparts (E = -923/-854 mV). Antiproliferation activities were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL was potent (EC = 0.080 μM) and selective (EC/EC = 25) for A549. Its linkage isomer CuL had equivalent A549 activity, but lower selectivity (EC/EC = 12.5). The isomers CuL and CuL were less potent with EC values of 1.9 and 0.19 μM and less selective with EC/EC ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity.