Synthesis and Anticancer Activity of Pentafluorobenzenesulfonamide Derivatives as Caspase-Dependent Apoptosis-Inducing Agents.

Arylsulfonamides are ubiquitous in a number of anticancer agents, and fluorine substitution on aromatic rings often improves drug profile. Herein, a series of novel pentafluorobenzenesulfonamide derivatives with different molecular scaffolds were readily synthesized and assessed for their antitumor activities against multiple cancer cell lines, including A549, HepG2, HuCCA-1, and MOLT-3. Dihydroimidazoline-containing analogue and its Diels-Alder cycloadducts exhibited enhanced cytotoxicity at micromolar range while the incorporation of other heterocyclic cores via nucleophilic substitution reaction resulted in diminished potency. Selected analogues were shown to induce the accumulation of cleaved forms of Casp-9, Casp-7 and PARP in cancer cells, indicating intrinsic apoptosis via a caspase-dependent process.