Structure-based strategies for synthesis, lead optimization and biological evaluation of N-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivatives as potential multi-target anticancer agents

As part of our research on developing multi-target small molecule anticancer agents, we designed, synthesized, and biologically evaluated a series of novel diversified analogues based on our thiadiazole-fused anthraquinone lead compound NSC745885. We initially screened our compounds based on their cytotoxicities against two prostate cancer cell lines (PC-3 and DU-145). Cytotoxicities of the selected compounds (3, 5, 6, 10, 11, 14, 15, 17, 18) were then evaluated using the single-dose testing against a panel of 60 cancer cell lines. Compounds which exceeded the threshold inhibition criteria (3, 6, 10, 11, 14, 17) were further evaluated using the five-dose cytotoxicity experiments against the panel of 60 cancer cell lines. Our compounds exhibited potent antiproliferative effects against the tested cancer cell lines with 50% growth inhibition (GI₅₀) values in the sub-micro molar range. Furthermore, 3 and 6 showed high selectivity towards the leukemia subpanel, whereas 6 showed high selectivity towards the prostate subpanel. Our potent compound 11 (RV59, NSC763967) showed broad-spectrum cytotoxicity against different types of cancer cells, while being less cytotoxic than doxorubicin towards different normal cells (SV-HUC-1, WMPY-1, and RWPE-1). COMPARE analysis of the cytotoxicity data indicated that 11 is similar to the apoptosis-based anticancer drugs. We confirmed the apoptotic effects of 11 by microscopy, Western blotting, and flow cytometry of treated cancer cells, and found that it caused cells to exhibit apoptotic morphology, inhibited cyclin D1 and COX-2 in a dose-dependent manner, and accumulated cells at the G₀/G₁ phase with reduction of cells in the S and G₂/M phases of cell cycle. Moreover, we tested the inhibition capabilities of our compounds towards Topoisomerases (TOP) using computational modeling and found that they are specific inhibitors to TOP1. Our data presented here presents our compounds as potential multi-target anticancer drugs.