Ligand and Linkage Isomers of Bis(ethylthiocarbamato) Copper Complexes with Cyclic C6H8 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 (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 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. CuL2a was potent ((EC50)-E-A549=0.080 mu M) and selective (IMR-90EC50/(EC50)-E-A549=25) for A549. Its linkage isomer CuL2b had equivalent A549 activity, but lower selectivity (IMR-90EC50/(EC50)-E-A549=12.5). The isomers CuL3a and CuL3b were less potent with (EC50)-E-A549 values of 1.9 and 0.19 M and less selective with IMR-90EC50/(A549)EC(50 )ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity.

Automated summary

A series of isomeric bis(alkylthiocarbamate) copper complexes were synthesized and evaluated for their antiproliferation activity. One of the complexes, CuL2a, showed potent activity and selectivity against lung adenocarcinoma cells.