Synthesis, cytotoxicity and structure-activity relationship of indolizinoquinolinedione derivatives as DNA topoisomerase IB catalytic inhibitors

Our previous studies reveal that indolizinoquinolinedione scaffold is a base to develop novel DNA topoisomerase 113 (TOPI) catalytic inhibitors. In this work, twenty-three novel indolizinoquinolinedione derivatives were synthesized. TOP1-mediated relaxation, nicking and unwinding assays revealed that three fluorinated derivatives 26, 28 and 29, and one N,N-trans derivative 46 act as TOPI catalytic inhibitors with higher TOPI inhibition (++++) than camptothecin (+++) and without TOPI-mediated unwinding effect. MTT assay against five human cancer cell lines indicated that the highest cytotoxicity is 20 for CCRF-CEM cells, 25 for A549 and DU-145 cells, 26 for HCT116 cells, and 33 for Huh7 cells with GI(50) values at nanomolar range. The drug-resistant cell assay indicated that compound 26 may mainly act to TOPI in cells and are less of Pgp substrates. Flow cytometric analysis showed that compounds 26, 28 and 29 can obviously induce apoptosis of HCT116 cells. Moreover, the structure-activity relationship (SAR) of indolizinoquinolinedione derivatives was analyzed. (C) 2018 Elsevier Masson SAS. All rights reserved.