Unsymmetrical bisacridines as anticancer drug candidates: structure-metabolism-activity relationships and design principles.

Unsymmetrical bisacridines (UAs) are a promising class of anticancer drug candidates. Due to their dual acridine-based architecture and structural asymmetry, they combine high biological activity with distinctive physicochemical, cellular, and metabolic properties. UAs have demonstrated activity against a broad range of cancer cell lines and in human cancer xenograft models, including models of breast, lung, colon, prostate, and pancreatic tumors, many of which are poorly responsive to conventional chemotherapy. However, their therapeutic potential depends not only on direct interactions with molecular targets but also on absorption, intracellular accumulation, metabolic conversion, and metabolite fate. This review summarizes current knowledge on three selected UAs, C-2028, C-2045, and C-2053, which differ in the substituents present in their acridine rings. Particular attention is given to their pH-dependent behavior, preferential accumulation in cancer cells, Phase I and Phase II metabolic pathways, and interactions with G-quadruplex DNA structures. Available evidence indicates that UA metabolism may have diverse biological consequences. For C-2028, glutathione conjugation and intracellular retention of the resulting metabolite suggest that metabolism may influence intracellular residence time and contribute to the overall cytotoxic response. In contrast, C-2045 undergoes glucuronidation followed by extracellular export, suggesting a more conventional detoxification and elimination route. These compound-specific differences indicate that metabolism can modulate UA efficacy, selectivity, and toxicological risk. This review integrates structural, ADME-related, metabolic, and biological data for selected UAs. It identifies metabolism-guided structure-activity considerations and outlines testable hypotheses for future UA optimization, particularly with respect to balancing intracellular retention, metabolic elimination, possible bioactivation, and reactive-metabolite liability.