Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

摘要

In our previous work, indolizinoquinolinedione derivative >1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound >1. Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including >8, 11–16, 18–21, 25, 26 and >28–30, are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that >14, 22 and >26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds >26, 28–30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound >26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range.