Ligand and Linkage Isomers of Bis(ethylthiocarbamato) Copper Complexes with Cyclic C6H8 Backbone Substituents: Synthesis, Characterization, and Antiproliferation Activity

Abstract

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 (H₂L²) and cyclohexyl (H₂L³) backbone substituents, which each yield a pair of linkage isomers. The thermodynamic products CuL^2a/3a have two imino N and two S donors resulting in three five-member chelate rings (555 isomers). The kinetic isomers CuL^2b/3b 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^II/I potentials (E_1/2 = -811/-768 mV vs. ferrocenium/ferrocene) and lower energy charge transfer bands than their 465 counterparts (E_1/2 = -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^2a was potent (^A549EC₅₀ = 0.080 μM) and selective (^IMR-90EC₅₀/^A549EC₅₀ = 25) for A549. Its linkage isomer CuL^2b had equivalent A549 activity, but lower selectivity (^IMR-90EC₅₀/^A549EC₅₀ = 12.5). The isomers CuL^3a and CuL^3b were less potent with ^A549EC₅₀ values of 1.9 and 0.19 μM and less selective with ^IMR-90EC₅₀/^A549EC₅₀ ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity.

Keywords: N2S2 ligands; antiproliferation activity; copper; ligand isomer; linkage isomer.