Our previous studies reveal that indolizinoquinolinedione scaffold is a base to develop novel DNA topoisomerase IB (TOP1) 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 TOP1 catalytic inhibitors with higher TOP1 inhibition (++++) than camptothecin (+++) and without TOP1-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 GI₅₀ values at nanomolar range. The drug-resistant cell assay indicated that compound 26 may mainly act to TOP1 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.

我们以前的研究表明，吲哚izinoquinolinedione支架是开发新型DNA拓扑异构酶IB（TOP1）催化抑制剂的基础。在这项工作中，合成了二十三种新颖的吲哚并喹啉二酮衍生物。TOP1介导的松弛，切口和退绕实验表明，3个氟化衍生物26，28和29，和一个N，N-反式衍生物46充当TOP1催化抑制剂具有较高TOP1抑制（++++）比喜树碱（+++ ），并且没有TOP1介导的放卷效果。针对五种人类癌细胞系的MTT分析表明，CCRF-CEM细胞的最高细胞毒性为20，A549和DU-145细胞的最高细胞毒性为25，HCT116细胞为26，而Huh7细胞为33，GI ₅₀值在纳摩尔范围内。耐药细胞分析表明，化合物26可能主要作用于细胞中的TOP1，并且是较少的Pgp底物。流表明，化合物流式细胞分析26，28和29可以明显地诱导细胞凋亡HCT116细胞的。此外，分析了吲哚izinoquinolinedione衍生物的构效关系（SAR）。