Anti-proliferative activity of dithiocarbamate salts: Synthesis and in vitro study

Dithiocarbamate (DTC) derivatives including S-alkylated compounds, metal-complexes, or the combination of some of these derivatives with known chemotherapeutic drugs have been extensively studied for their anti-tumor activities. Interestingly, the anti-proliferative activities of DTC salts have not been studied. A new series of DTC salts including alkyl-, morpholinyl-, and benzyl-containing derivatives was synthesized. The compounds were assessed for their cytotoxic activity against four human cancer cell lines (MCF7, ES2, HSC3, and RKO). Most of the synthesized compounds demonstrated excellent to moderate activity against MCF7, ES2, and HSC3 cancer cells. However, all the compounds showed low activity against RKO cell line (IC₅₀ > 10 μM). Notably, compound 1 with methyl groups showed the most potent anti-proliferative activity against the three cell lines, followed by compounds 2 and 6 with ethyl and morpholinyl groups, respectively. Importantly, the anti-proliferative activity significantly decreased as the size of the N-substituents increased. Compounds 4, 5, and 7 containing butyl, isobutyl, and benzyl groups, respectively, exhibited low activity against all cell lines (IC₅₀ > 10 μM). The three leading compounds (1, 2, and 6) induced apoptosis in HSC3 head and neck cancer cells as evident by cell shrinkage, nuclear fragmentation, and upregulation of caspase 3, 8, and 9 expression.