Novel 2-alkythio-4-chloro- N -[imino(heteroaryl)methyl]benzenesulfonamide Derivatives: Synthesis, Molecular Structure, Anticancer Activity and Metabolic Stability.

A series of novel 2-alkythio-4-chloro- N -[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 8 - 24 , were synthesized in the reaction of the N -(benzenesulfonyl)cyanamide potassium salts 1 - 7 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds, 11 - 13 , molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC 50 : 6-7 μM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC 50 : 18-20 μM). It was found that the anti-proliferative effects of 11 , 12 and 13 were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t ½ for 11 - 13 in the range of 9.1-20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites.