Ligand and Linkage Isomers of Bis(ethylthiocarbamato) Copper Complexes with Cyclic C(6)H(8) 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 (H(2)L(2)) and cyclohexyl (H(2)L(3)) 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 ((A549)EC(50) = 0.080 μM) and selective ((IMR-90)EC(50)/(A549)EC(50) = 25) for A549. Its linkage isomer CuL(2b) had equivalent A549 activity, but lower selectivity ((IMR-90)EC(50)/(A549)EC(50) = 12.5). The isomers CuL(3a) and CuL(3b) were less potent with (A549)EC(50) values of 1.9 and 0.19 μM and less selective with (IMR-90)EC(50)/(A549)EC(50) ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity.