Abstract
Recently, anthraquinone scaffolds have attracted increasing amounts of attention as sources for effective drug synthesis for the treatment of various diseases. Here, we demonstrate the potential of nine anthraquinone amino-derivatives (AADs) as anticancer agents. We synthesized nine Schiff bases (1-9) using an anthraquinone scaffold and amino acids. We applied in silico analysis by performing molecular docking against the anticancer drug target human serine/threonine p21-activated kinase 4 (PAK4) and compared them with the recently developed PAK4 inhibitor PF-3758309. Compounds 5and 8 showed docking properties comparable to that of PF-3758309 at two binding sites located in the C-terminal domain of PAK4. Compound 5, a tryptophan-based anthraquinone derivative, had docking scores of -9.3 and -8.7 kcal/mol at two different identified cavities, cav-1 and cav-4, respectively, exceeding that of the control PF-3758309 for both cavities. Additional optimization of the indole moiety of 5gave rise to 5b, resulting in high drug likeness (0.74) and comparable binding properties to cav-1 (-8.6 kcal/mol) and the highest achievable binding affinity to cav-4, with an average of -9.7 kcal/mol, indicating a potential allosteric inhibitory effect via cav-4. Our molecular dynamics simulation analysis of the top hits and the control compound provides important insights into the mechanism of action of these drug candidates. Additionally, all the compounds exhibited promising pharmacokinetic and toxicity properties, as revealed by the ADMET profiles, urging the need for comprehensive in vitro and in vivo antitumor characterization. Our results also indicate that cav-4 may serve as a target for designing specific allosteric inhibitors against PAK4-overexpressing cancer cells, suggesting its potential application in adjuvant cancer treatment.