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

doi:10.1016/j.ejmech.2021.113916

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. Epub 2021 Oct 11.

Authors

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
DNA / chemistry
DNA Topoisomerases, Type I / metabolism*
DNA Topoisomerases, Type II / metabolism*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Halogens / chemistry
Halogens / pharmacology*
Humans
Indenes / chemical synthesis
Indenes / chemistry
Indenes / pharmacology*
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Poly-ADP-Ribose Binding Proteins / metabolism*
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship
Topoisomerase Inhibitors / chemical synthesis
Topoisomerase Inhibitors / chemistry
Topoisomerase Inhibitors / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Halogens
Indenes
Poly-ADP-Ribose Binding Proteins
Pyridones
Topoisomerase Inhibitors
DNA
calf thymus DNA
DNA Topoisomerases, Type I
TOP1 protein, human
DNA Topoisomerases, Type II
TOP2A protein, human