Steroidal Scaffolds as Anticancer Agents: Evolution, FDA Approvals, Synthetic Derivatives, SAR Profiles, and...

Steroidal scaffolds, owing to their inherent structural rigidity, membrane permeability, and receptor affinity, have emerged as a critical class of molecules in anticancer drug development. This manuscript comprehensively explores the development, FDA-approved drugs such as dexamethasone, prednisone, and abiraterone acetate, synthetic innovations, and clinical potential of steroidal derivatives in anticancer therapy. Glucocorticoids and hormone modulators remain foundational in treating hematologic- and hormone-dependent cancers. At the same time, recent synthetic hybrids, including triazoles, isatins, pyrimidines, and benzisoselenazolones, have shown enhanced potency and selectivity across solid tumor models. The paper underscores the integration of steroids with potential anticancer activity, kinase inhibitors, and bioactive heterocycles to overcome pharmacokinetic limitations and hormone resistance. Several novel steroidal derivatives have demonstrated potent anticancer activity, as evidenced by low IC₅₀ values: compound 29 (0.34 µM), 30 (0.25 µM and 0.28 µM), 32 (0.00083, 0.029, and 0.056 µM), and 36 (0.34 µM). These findings underscore their strong cytotoxic potential against cancer cell lines. The central perspective emphasizes the resurgence of steroid-based drug design in the precision medicine era, especially in the context of emerging synthetic strategies and their translational viability in resistant and metastatic cancer phenotypes. Furthermore, several investigational steroid-drug combinations are currently being evaluated in clinical trials for advanced-stage cancers, including prostate, breast, and head and neck malignancies, underscoring their translational potential. This review highlights both the therapeutic promise and future directions of steroidal anticancer agent, reinforcing their value as a cornerstone in the development of targeted and supportive cancer therapy.