Design, Synthesis, Biological Evaluation, and In Silico Study of Aspirin-Sulfonamide Hybrids as Potential Anticancer Agents.

Aspirin's potential as a cancer treatment had garnered significant attention over the past 50 years. Presently, researchers are focused on structurally modifying aspirin to enhance its anticancer efficacy. In this study, aspirin was employed as the parent compound, and N-acylation of aspirin chloride with piperazine-sulfonamide hybrids was utilized to efficiently synthesize promising anticancer agents 3. Biological assays and structure-activity relationship analysis demonstrated that the incorporation of thiophene groups significantly enhanced the anticancer activity of aspirin. Among all eight human cancer cells treated, hybrid 3k, containing a bromothiophene structure, was the most effective against human non-small-cell lung cancer (A549) cells (IC50 = 36 μM), exhibiting over 33-fold greater toxicity than parent aspirin (IC50 > 1200 μM) and a higher selectivity index (SI = 6). Mechanistic studies revealed that hybrid 3k induced apoptosis in A549 cells and arrested the cell cycle at the G0/G1 phase. Molecular docking analysis and COX-2 inhibition assay indicated that hybrid 3k likely exerts its anticancer effects through the inhibition of COX-2 protein. These findings underscore the potential of hybrid 3k as a novel therapeutic agent for non-small-cell lung cancer and its contribution to expanding the antitumor scope of aspirin.