Hit-to‑lead optimization of new carbazoles as potential anticancer agents via targeting human topoisomerase II.

Prostate and breast cancers are the major concerns among cancer patients. This study represents the development of new carbazoles as anticancer agents by interfering with topoisomerases II (topoII). Fifteen rationally designed carbazoles (4a-4o) were initially synthesized and screened for anticancer activities against different cancer cell lines. The promising hit compound 4f was further optimized by modifying the carbazole scaffold at positions 1, 3, 4, and 9, which led to the synthesis of its derivatives 5a-5j, 6a-6d and 7a-7d. Interestingly, 5a (IC = 8.47 ± 0.29 μM) and 6a (IC = 5.35 ± 0.30 μM) showed selective and improved anticancer activities than 4f (IC = 10.20 ± 0.44 μM and 8.564 ± 0.55 μM) in MCF-7 and PC-3 cells, respectively. Both compounds increased the ROS generation, depolarized the mitochondrial membrane, induced apoptosis via increased relative Bax/Bcl2 ratio, and arrested the cell cycle at G2/M phase. The selective human topoII inhibition further supported their anticancer mechanism. The in silico molecular docking and MD simulation studies aided their binding analysis in topoII and claimed them as potential topoII inhibitors.