Exploration of Benzo[b]carbazole-6,11-diones as anticancer agents: Synthesis and studies of hTopoIIα inhibition and apoptotic effects

Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoII alpha inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative C-N and Pd-catalyzed C-C bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoII alpha inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- x beta signaling cascade, relatively less cytotoxicity to normal cells, and hTopoII alpha inhibition with more efficiency compared to an anticancer drug etoposide.

Automated summary

Two series of compounds were synthesized and screened against cancer cells, with some showing significant apoptotic anti-proliferation effects on cancer cells; they also exhibited relatively less cytotoxicity to normal cells and showed more efficiency in hTopoII alpha inhibition compared to the anticancer drug etoposide.