Sulfonamide derivatives as tubulin polymerization inhibitors: advances in structural mechanisms, structure–activity relationships, and therapeutic potential in cancer treatment

Abstract

Cancer has been ranked as one of the major causes of death globally, with a rising trend in its incidence and resistance towards existing chemotherapeutic drugs. These necessitate the development of novel therapeutic strategies for the treatment of this deadly disease. Microtubules, which are integral to cell division, are potential target sites in drug discovery for anticancer drugs. Sulfonamide derivatives have emerged as potential and privileged scaffolds in medicinal chemistry, exhibiting significant potential in inhibiting tubulin polymerization due to their high binding affinity at the colchicine binding site of tubulin. Binding to the colchicine site rapidly induces G2/M-phase cell cycle arrest and ultimately cell death in rapidly proliferating cancer cells. The past decade has seen significant advancements in academia and the pharmaceutical industry in the development of sulfonamide-based anticancer agents including natural product hybrids, synthetic analogues and molecular conjugates, which have shown activity in multidrug-resistant cancer cells while exhibiting favorable pharmacokinetics. This review summarizes recent insights into structural mechanisms and structure–activity relationship (SAR) data, along with the latest preclinical and clinical advances. Several promising compounds that show potential to overcome the limitations of current microtubule-targeting agents are highlighted. Collectively, the evidences position sulfonamide derivatives as robust scaffolds for the development of next-generation cancer therapeutics targeting tubulin polymerization.