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) (CuL) and (1-phenylpropane-1-one-(N-methylthiosemicarbazonato)-2-imine-(O-ethylthiocarbamato))copper(II) (CuL) along with (1-propane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL). Complexes CuL and CuL differ in the positions of the pendent thiosemicarbazone (TSC) and alkylthiocarbamate (ATC) moieties on the 1-phenylpropane backbone. Complex CuL employs a propane backbone with the TSC in the 2-position as in CuL. The isomer pair CuL and CuL have equivalent electronic environments with indistinguishable Cu potentials (E = -0.86 V vs. ferrocenium/ferrocene) and electron paramagnetic resonance (EPR) spectra (g = 2.26, g = 2.08). The electronic structure of CuL has a similar E of -0.84 V and identical EPR parameters to CuL. 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 were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL had the highest A549 activity (EC = 0.065 μM) and selectivity (EC/EC = 20). The constitutional isomer CuL displayed decreased A549 activity (0.18 μM) and selectivity (10.6). The complex CuL displayed activity (0.009 μM) similar to CuL 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 did not induce reactive oxygen species (ROS) generation.