Novel N-(2-Mercaptobenzenesulfonyl)guanidine Derivatives Modified by Nitrogen-containing Heterocycles – Synthesis and Antiproliferative Activity Against Human Cancer Cell Lines

Benzenesulfonylguanidine derivatives have been known to inhibit growth of different types of human cancer cell lines. According to this fact, new compounds with structures based on benzenesulfonylguanidine scaffold and modified by important pharmacophores such as morpholine, 4-methylpiperazine or piperidine, have been designed and synthesized. The planned
N-(2-mercaptobenzenesulfonyl)guanidine derivatives  have been obtained by reaction of the appropriate N-(2-mercaptobenzenesulfonyl)cyanamide potassium salt with
1-aminopiperidine, 4-aminomorpholine or 1-amino-4-methylpiperazine; p-toluenesulfonic acid has been used as a protonating agent. The obtained compounds have been evaluated in MTT assay for an antiproliferative activity against human cancer cell lines HCT-116 (colon carcinoma), MCF-7 (breast cancer) and HeLa (cervical cancer). The results indicated that compounds containing the 4-methylpiperazine ring were the most potent growth inhibitors. The obtained IC₅₀ values for these derivatives were lower than 35 μM against all tested cancer cell lines, with the best activity at level of IC₅₀ ≤ 15 μM for compound with a methyl group at the position 5, and a (2-fluorophenyl)methylthio group at the position 2 of benzenesulfonyl scaffold.  Moderate antiproliferative effect (IC₅₀ ~ 40 μM) was observed for derivatives containing a piperidine residue. Compounds with a morpholine fragment, in contrast, did not show significant growth inhibition.