Development of a metabolically stable topoisomerase I poison as anticancer agent

We have recently reported a new chemotype of a potent topoisomerase I poison with compound 1 as a potential anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1, we report design and synthesis of metabolically stable Top1 poison 3. Newly identified Top1 poison 3 exhibits t(1/2) of 69.1 min in human liver microsomes in comparison to compound 1 with t(1/2) of 9.9 min. Molecular dynamic study of the newly optimized Top1 poison 3 was performed to get the insight into the stability of the binding pose in the active site. Compound 3 was able to trap DNA-Top1 cleavage complex and found to be less cytotoxic in non-cancerous cell line as compared to compound 1. (C) 2020 Elsevier Masson SAS. All rights reserved.