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

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 CuII/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 CuL1, 2. Single crystal X-ray diffraction studies confirm a consistent donor environment with no substantial variation in the Cu N or Cu S bond distances and angles between the complexes. The antiproliferation activities of the CuL1–3 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 (A549EC 50 = 0.065 μM) and selectivity (IMR-90EC 50 /A549EC 50 = 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 CuL1–3 did not induce reactive oxygen species (ROS) generation. A triad of Cu(II) complexes, including a pair of constitutional isomers, with spectroscopically equivalent CuN 2 S 2 core electronic structures display different antiproliferation activity and selectivity dependent on structural features. [Display omitted] • Electronic and structural effects on antiproliferation activity for Cu(II) complexes including constitutional isomers. • Equivalent CuN 2 S 2 electronic structures with different physical structures substantially changes activity and selectivity. • Influence of specific functional groups and their relative positioning on activity and selectivity. • Small (Me, H) backbone substituent on the thiosemicarbazone side of the molecule improve activity. • Complexes with a backbone H group show no selectivity between A549 and IMR-90 cells. [ABSTRACT FROM AUTHOR]