Di-indenopyridines as topoisomerase II-selective anticancer agents: Design, synthesis, and structure-activity relationships

Topoisomerases are key molecular enzymes responsible for altering DNA topology, thus they have long been considered as attractive targets for novel chemotherapeutic agents. Topoisomerase type II (Topo II) catalytic inhibitors embrace a fresh perspective meant to get beyond drawbacks caused by topo II poisons, such as cardiotoxicity and secondary malignancies. Based on previously reported 5H-indeno[1,2-b]pyridines, here we presented new twenty-three hybrid di-indenopyridines along with their topo I/II & alpha; inhibitory and antiproliferative activity. Most of the prepared 11-phenyl-diindenopyridines showed negligible topo I inhibitory activity, showing selectivity over topo II. Among the series, we finally selected compound 17, which displayed 100 % topo II & alpha; inhibition at 20 & mu;M concentration and comparable antiproliferative activity against the tested cell lines. Through competitive EtBr displacement assay, cleavable complex assay, and comet assay, compound 17 was finally determined as a non-intercalative catalytic topo II & alpha; inhibitor. The findings in this study highlight the significance of phenolic, halophenyl, thienyl, and furyl groups at the 4-position of the indane ring in the design and synthesis of di-indenopyridines as potent catalytic topo II & alpha; inhibitors with remarkable anticancer effects.

Automated summary

Topoisomerases are important enzymes for altering DNA topology and have been considered as attractive targets for chemotherapeutic agents. In this study, we presented new di-indenopyridine compounds with inhibitory activity against topoisomerase I/II and alpha. Compound 17 showed 100% inhibition of topoisomerase II and alpha at 20 μM concentration, as well as comparable antiproliferative activity against tested cell lines. These findings highlight the significance of specific groups at the 4-position of the indane ring in designing potent catalytic topoisomerase II and alpha inhibitors with anticancer effects.