Aromatic Sulfonamides Emerge as a Promising Frontier in Advanced Cancer Therapy.

INTRODUCTION/OBJECTIVE: Current cancer chemotherapy is limited by severe adverse effects, poor selectivity toward malignant cells, and the emergence of multidrug resistance, highlighting the need for novel therapeutic strategies with enhanced potency and safety. Sulfonyl-containing compounds and sulfonamide derivatives have attracted sustained attention as anticancer scaffolds because of their structural diversity, favorable physicochemical properties, and broad pharmacological profiles. This review critically examines how structural variation within aromatic sulfonamides controls target engagement, anticancer activity, and translational potential. Rather than cataloguing individual derivatives, it integrates cross-family structure-activity relationships with mechanistic evidence involving carbonic anhydrases, tubulin dynamics, survival signaling, apoptosis, and tumorassociated metabolic adaptation. METHODS: Recent experimental and preclinical studies were reviewed, with special emphasis on sulfonyl and sulfonamide derivatives as multifunctional pharmacophores and their emerging role in cancer therapy, supported by extensive chemical and pharmacological evidence. Emphasis was placed on heterocyclic sulfonyl compounds and macrocyclic hybrid systems. RESULTS: Several sulfonamide derivatives have demonstrated potent antiproliferative activity against a broad range of human cancer cell lines, including MCF-7 and MIA PaCa-2, by interacting with multiple targets and disrupting pathways involved in tumor growth and survival. Calixarenesulfonyl hybrids demonstrate selective and potent cytotoxicity against several cancer cell lines, including breast and pancreatic cancer models. These compounds inhibit tubulin dynamics, reduce the proliferation of multiple human cancer cell lines, induce apoptosis, and modulate molecular targets associated with the phosphoinositide 3-kinase/protein kinase B signaling pathway. The clinical success of sulfonamide-containing agents further validates this pharmacophore in oncology. DISCUSSION: The available evidence indicates that structural optimization of aromatic sulfonamides can improve antiproliferative activity and target selectivity, although cellular potency alone is insufficient to establish therapeutic relevance. Direct target validation, mechanistic characterization, tumor selectivity, and pharmacokinetic assessment remain necessary to distinguish pharmacologically relevant activity from non-specific cytotoxicity. CONCLUSION: Aromatic sulfonamides constitute a chemically adaptable platform from which compounds acting on carbonic anhydrases, tubulin, survival signaling, and apoptosis-related processes have been developed. The available evidence supports their continued investigation in anticancer drug discovery; however, multi-target activity should be considered advantageous only when target engagement, tumor selectivity, and resistance-relevant effects are experimentally distinguished from non-specific cytotoxicity. Future development will depend on biomarker-guided evaluation, direct mechanistic validation, and early assessment of pharmacokinetic and safety liabilities.