Design, synthesis, and biological evaluation of novel steroidal selenosemicarbazone derivatives as potent antitumor agents.

The development of novel chemotherapeutic agents with high efficacy and low toxicity remains a critical challenge in oncology. In this study, a novel series of steroidal selenosemicarbazone derivatives were designed and synthesized through the selenium functionalization of diverse steroid scaffolds. Key ketone intermediates derived from cholesterol, dehydroepiandrosterone (DHEA), estrone, and pregnenolone were condensed with various selenosemicarbazides to achieve structural diversification across the steroid nucleus. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines. Most compounds exhibited broad-spectrum cytotoxicity, among which compound 17c, based on the DHEA scaffold, showed superior potency against MCF-7 breast cancer cells(IC50 = 4.80 ± 0.43 μM)and high selectivity over normal cells. Mechanism-of-action studies revealed that 17c induces mitochondrial-mediated apoptosis, characterized by the loss of mitochondrial membrane potential, activation of caspase-9, and G2/M phase cell cycle arrest. Molecular docking simulations implicated glutathione reductase (GR) as a potential molecular target, suggesting that the binding of 17c to GR may initiate the observed mitochondrial dysfunction. Furthermore, the concentration-dependent suppression of cell proliferation, migration, and clonogenic survival by 17c was confirmed through a suite of functional assays. Collectively, this work identifies 17c as a promising lead compound with a clarified mechanistic profile for the development of efficient and low-toxicity anticancer agents.