Stanolone-1,2,3-Triazole derivatives: Synthesis, DNA damage in tumor cells and anti-prostate Cancer activity study

Abstract

1,2,3-Triazole skeleton may act as both a hydrogen bond acceptor and a linker connecting different structures, and androgens bearing 1,2,3-triazole structures exhibit interesting biological activities against prostate cancer. Based on this rationale, various substituted 1,2,3-triazole groups were introduced to stanolone via click chemistry, and a total of 32 stanolone derivatives (13a - 13r and 14a–14n) were obtained under mild conditions. Their in vitro inhibitory activities against two prostate cancer cell lines, PC3 and DU145, were evaluated, and a preliminary structure-activity relationship (SAR) was established. Compounds 14e, 14f, and 14 k exhibited significant inhibitory effects, with IC₅₀ values of 12.33 μM, 6.69 μM, and 13.83 μM, respectively, against PC3 cells, and 18.55 μM, 5.67 μM, and 5.08 μM, respectively, against DU145 cells. These compounds were found to induce mitochondrial apoptosis in PC3 and DU145 cells. Further investigation revealed the activation of the γ-H2AX signaling pathway, leading to DNA damage in tumor cells. Notably, compound 14 k also demonstrated promising antitumor efficacy in a DU145 xenograft mouse model, and showing no cytotoxicity to normal human renal epithelial cells (HK−2), human liver cells (LO2), or human lung epithelial cells (BESA-2b) in vitro, indicating its potential as a lead compound for future antitumor drug study.