New N-Benzenesulfonylguanidine Derivatives and Their Selective Growth Inhibition of Human Breast Cancer Cell Line MCF-7 and Colon Carcinoma HCT-116 ^†

Abstract

Our previous research proved that benzenesulfonylguanidine derivatives display significant cytotoxic activity against human cancer cells. Here, we describe new 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines with cytotoxic activity against HCT-116 and MCF-7 cells. The planned derivatives were obtained by a two-step synthesis. The starting substrates were 1-(2-alkylthio-4-chloro-5-methyl)benzenesulfonyl)-3-aminoguanidines 1–4, which were transformed into 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-3-[(2-chloroacetyl)amino]guanidines 5–8 by a reaction with chloroacetyl chloride. In the next step, the derivatives 5–8 were reacted with potassium thiocyanate, yielding 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-3-(2-imino-4-oxothiazolidine-3-yl)guanidines 9–12. The synthesized derivatives 5–12 were evaluated in vitro by MTT assays for their activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7, and cervical cancer HeLa. The activity against non-cancerous human epidermal keratinocyte line HaCaT was also examined. The data indicate that compounds 5–8 inhibit the growth of cancer cells more strongly than derivatives 9–12. The selective cytotoxic effect against HCT-116 cells was found for benzenesulfonylguanidine 6 containing a 2-(trifluoromethyl)benzylthio group at position two of the benzenesulfonyl scaffold. The IC₅₀ value was 13 μM, while IC₅₀ for HaCaT cells, it was 48 μM. Good selectivity was also observed for compound 7, with a 2-chloromethylbenzylthio substituent, against HCT-116 and MCF-7 cells (IC₅₀ = 12 and 19 μM, respectively, for HCT-116 and MCF-7 cells, IC₅₀ = 47 μM for HaCaT cells). Among compounds 9–12, only compound 9 showed moderate but selective cytotoxicity against MCF-7 cells, with IC₅₀ = 18 μM compared with IC₅₀ = 54 μM for HaCaT cells.