Identification of new halogen-containing 2,4-diphenyl indenopyridin-5-one derivative as a boosting agent for the anticancer responses of clinically available topoisomerase inhibitors

Soo Yeon Hwang, Aarajana Shrestha, Seojeong Park, Ganesh Bist, Surendra Kunwar, Tara Man Kadayat, Haejin Jang, Minjung Seo, Naeun Sheen, Seojeong Kim, Kyung Hwa Jeon, Eung Seok Lee, Youngjoo Kwon

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2 Scopus citations

Abstract

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F−, Cl−, Br−, CF3− and OCF3−)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl−, Br−, and CF3− groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.

Original languageEnglish
Article number113916
JournalEuropean Journal of Medicinal Chemistry
Volume227
DOIs
StatePublished - 5 Jan 2022

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