Copper bis(thiosemicarbazone) (CuBTSC) complexes such as CuATSM and CuGTSM have received significant attention as diagnostic and therapeutic agents. For CuBTSC complexes with antiproliferation activity against cancer cells, various mechanisms of action have been proposed including the ligand serving as an ionophore to deliver Cu(II) into the cell where it is reduced to Cu(I) leading to the formation of reactive oxygen species. Recently, we reported a series of Cu(II) complexes based on bis(alkylthiocarbamate) ligands as pendent alkoxy derivatives of CuBTSCs and the antiproliferation activity of metal complexes with hybrid alkylthiocarbamate-thiosemicarbazones. In this study, a pair of linakge isomers (CuL⁴⁶⁵and CuL⁵⁵⁵) was derived by reacting phenylglyoxal bis(ethylthiocarbamate) with copper acetate monohydrate and characterized by IR spectroscopy, UV-Visible spectroscopy and single crystal X-ray crystallography. Linkage isomers are compounds with the same metal-ligand combination but with different coordinating donor atoms. Since linkage isomers have different physical and electronic structures, they may be expected to have different cellular uptake and antiproliferation activity if the intact metal complex was responsible for biological activity. Solution studies confirm the two isomers do not interconvert in the absence of strong acid and extended heating making them ideal for the first study of isolated linkage isomers on antiproliferation activity. The antiproliferation activity of the isomer pair was evaluated against lung adenocarcinoma cell line (A549) and in a nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. The isomers CuL⁵⁵⁵ and CuL⁴⁶⁵ possessed GI₅₀ values of 0.10 and 0.14 µM for A549 and 1.4 and 0.78 µM for IMR-90, respectively. Comparison with related complexes suggests that the biological activity may be related to pendent functional groups that influence shape, polarity, and potential interactions with cellular targets.

Sarah Andres

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