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.
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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DNA / chemistry
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DNA Topoisomerases, Type I / metabolism*
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DNA Topoisomerases, Type II / metabolism*
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Female
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Halogens / chemistry
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Halogens / pharmacology*
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Humans
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Indenes / chemical synthesis
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Indenes / chemistry
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Indenes / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Poly-ADP-Ribose Binding Proteins / metabolism*
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Pyridones / chemical synthesis
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Pyridones / chemistry
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Pyridones / pharmacology*
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Structure-Activity Relationship
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Topoisomerase Inhibitors / chemical synthesis
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Topoisomerase Inhibitors / chemistry
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Topoisomerase Inhibitors / pharmacology*
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Halogens
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Indenes
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Poly-ADP-Ribose Binding Proteins
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Pyridones
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Topoisomerase Inhibitors
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DNA
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calf thymus DNA
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DNA Topoisomerases, Type I
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TOP1 protein, human
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DNA Topoisomerases, Type II
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TOP2A protein, human