Physical structure of constitutional isomers influences antiproliferation activity of thiosemicarbazone-alkylthiocarbamate copper complexes

Abstract

A series of hybrid thiosemicarbazone-alkylthiocarbamate copper complexes with similar electronic environments but distinct physical structures have been prepared, characterized, and evaluated for antiproliferation activity. The complexes include the constitutional isomers (1-phenylpropane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL¹) and (1-phenylpropane-1-one-(N-methylthiosemicarbazonato)-2-imine-(O-ethylthiocarbamato))copper(II) (CuL²) along with (1-propane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL³). Complexes CuL¹ and CuL² differ in the positions of the pendent thiosemicarbazone (TSC) and alkylthiocarbamate (ATC) moieties on the 1-phenylpropane backbone. Complex CuL³ employs a propane backbone with the TSC in the 2-position as in CuL¹. The isomer pair CuL¹ and CuL² have equivalent electronic environments with indistinguishable Cu^II/I potentials (E_1/2 = -0.86 V vs. ferrocenium/ferrocene) and electron paramagnetic resonance (EPR) spectra (g_∥ = 2.26, g_⊥ = 2.08). The electronic structure of CuL³ has a similar E_1/2 of -0.84 V and identical EPR parameters to CuL^{1, 2}. Single crystal X-ray diffraction studies confirm a consistent donor environment with no substantial variation in the CuN or CuS bond distances and angles between the complexes. The antiproliferation activities of the CuL^1-3 were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL¹ had the highest A549 activity (^A549EC₅₀ = 0.065 μM) and selectivity (^IMR-90EC₅₀/^A549EC₅₀ = 20). The constitutional isomer CuL² displayed decreased A549 activity (0.18 μM) and selectivity (10.6). The complex CuL³ displayed activity (0.009 μM) similar to CuL¹ but with a lack of selectivity (1.0). Cellular copper loading determined by ICP-MS was consistent with the activity and selectivity trends. The complexes CuL^1-3 did not induce reactive oxygen species (ROS) generation.

Keywords: Alkythiocarbamate; Antiproliferation activity; Constitutional isomers; Copper; N(2)S(2) ligands; Thiosemicarbazone.