Synthesis of acridone deivatives as potential topoisomerase I enzyme inhibitors and anti-cancer agents

Human topoisomerases are the ubiquitous proteins solving topological problems of DNA during cellular processes. Torsional stress is generated in DNA double helix during replication, transcription, recombination and repair which is relieved by nicking of the strands by topoisomerases. These nicks are later resealed. Camptothecin and its synthetic derivatives, which were first discovered as topoisomerase I enzyme inhibitors, have several limitations in their use in cancer chemotherapy. Therefore, intensive research in developing non-camptothecin derivatives has been initiated. In our research work we have tried to synthesize acridone derivatives with potential anti-cancer activity. Acridone derivatives with suitable substituents that can enhance the binding of our target compound in the topoisomerase-DNA cleavage complex were synthesized. Copper catalyzed ligand free, cross-coupling of a suitable indole derivative was attempted with aryl halides to synthesize a target acridone derivative that has been shown through molecular modeling to bind in the topoisomerase I cleavage complex by intercalating between the base pairs.