2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2022 Jan 5:227:113916. doi: 10.1016/j.ejmech.2021.113916.
Soo-Yeon Hwang 1,  Aarajana Shrestha 2,  Seojeong Park 1,  Ganesh Bist 2,  Surendra Kunwar 2,  Tara Man Kadayat 2,  Haejin Jang 1,  Minjung Seo 1,  Naeun Sheen 1,  Seojeong Kim 1,  Kyung-Hwa Jeon 1,  Eung-Seok Lee 3,  Youngjoo Kwon 4
Affiliations

Affiliations

  • 1 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 2 College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
  • 3 College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea. Electronic address: eslee@yu.ac.kr.
  • 4 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
PMID: 34678573 DOI: 10.1016/j.ejmech.2021.113916
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.

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