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

Abstract

AbstractA 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 CuL2a/3a have two imino N and two S donors resulting in three five‐member chelate rings (555 isomers). The kinetic isomers CuL2b/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 CuII/I potentials (E1/2=−811/−768 mV vs. ferrocenium/ferrocene) and lower energy charge transfer bands than their 465 counterparts (E1/2=−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. CuL2a was potent (A549EC50=0.080 μM) and selective (IMR‐90EC50/A549EC50=25) for A549. Its linkage isomer CuL2b had equivalent A549 activity, but lower selectivity (IMR‐90EC50/A549EC50=12.5). The isomers CuL3a and CuL3b were less potent with A549EC50 values of 1.9 and 0.19 M 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.