Discovery and Biological Evaluations of Halogenated 2,4-Diphenyl Indeno[1,2- b]pyridinol Derivatives as Potent Topoisomerase IIα-Targeted Chemotherapeutic Agents for Breast Cancer

Tara Man Kadayat, Seojeong Park, Aarajana Shrestha, Hyunji Jo, Soo Yeon Hwang, Pramila Katila, Ritina Shrestha, Mahesh Raj Nepal, Keumhan Noh, Sang Kyoon Kim, Woo Suk Koh, Kil Soo Kim, Yong Hyun Jeon, Tae Cheon Jeong, Youngjoo Kwon, Eung Seok Lee

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13 Scopus citations

Abstract

With the aim of developing new effective topoisomerase IIα-targeted anticancer agents, we synthesized a series of hydroxy- and halogenated 2,4-diphenyl indeno[1,2-b]pyridinols using a microwave-assisted single step synthetic method and investigated structure-activity relationships. The majority of compounds with chlorophenyl group at 2-position and phenol group at the 4-position of indeno[1,2-b]pyridinols exhibited potent antiproliferative activity and topoisomerase IIα-selective inhibition. Of the 172 compounds tested, 89 showed highly potent and selective topoisomerase IIα inhibition and antiproliferative activity in the nanomolar range against human T47D breast (2.6 nM) cancer cell lines. In addition, mechanistic studies revealed compound 89 is a nonintercalative topoisomerase II poison, and in vitro studies showed it had promising cytotoxic effects in diverse breast cancer cell lines and was particularly effective at inducing apoptosis in T47D cells. Furthermore, in vivo administration of compound 89 had significant antitumor effects in orthotopic mouse model of breast cancer.

Original languageEnglish
Pages (from-to)8194-8234
Number of pages41
JournalJournal of Medicinal Chemistry
Volume62
Issue number17
DOIs
StatePublished - 12 Sep 2019

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