Thiazolidinedione Derivatives as Anticancer Agents: Synthetic Strategies, SAR, and Therapeutic Potential

Cancer is the second most common cause of mortality after cardiovascular diseases. Over the years, many chemotherapeutic agents have been developed, but the lack of target specificity and selectivity, toxicity to normal cells, and the problem of developing resistance limit their clinical usefulness. This has prompted the search for novel, safer, effective, and highly specific anticancer agents. Thiazolidinedione, a sulfur and nitrogen-containing five-membered heterocyclic ring, has shown promising anticancer potential in preclinical studies. Substitutions at different positions on the thiazolidinedione scaffold can overcome the problem of toxicity and drug resistance by targeting cancer with various mechanisms of action. This includes promoting apoptosis of the cancer cells, inhibiting signaling pathways, and cell proliferation in cancers by the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). The thiazolidinedione derivatives also act by inhibiting glyoxalase, TopI/II, GLUT, Bcl2, Ras/Raf, and tyrosine kinase involved in cancer pathogenesis. This review discusses the recent developments in synthetic strategies of thiazolidinedione scaffolds; their mechanism of action, anticancer potential, and structure–activity relationships (SAR) will provide guidance for future directions in cancer research. The recent advancements in the development of thiazolidinedione derivatives as anticancer agents will pave the way for medicinal chemists to direct the synthesis of novel thiazolidinedione derivatives for future clinical use.