Abstract
A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the β over α isoform and with EC50 of 30-50 nM in cell-based and direct binding assays.
Keywords:
Cancer; Drug development; Estrogen receptor agonist; SERBA.
Copyright © 2018 Elsevier Masson SAS. All rights reserved.
MeSH terms
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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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Crystallography, X-Ray
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Cycloheptanes / chemical synthesis
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Cycloheptanes / chemistry
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Cycloheptanes / pharmacokinetics
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Cycloheptanes / pharmacology*
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Estrogen Receptor beta / agonists*
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Estrogens / chemical synthesis
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Estrogens / chemistry
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Estrogens / pharmacology*
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Humans
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MCF-7 Cells
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Methanol / chemical synthesis
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Methanol / chemistry
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Methanol / pharmacokinetics*
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Models, Molecular
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Molecular Structure
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Phenols / chemical synthesis
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Phenols / chemistry
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Phenols / pharmacology*
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Structure-Activity Relationship
Substances
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4-(4-hydroxyphenyl)cycloheptanemethanol
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4-cycloheptylphenol
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Antineoplastic Agents
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Cycloheptanes
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Estrogen Receptor beta
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Estrogens
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Phenols
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Methanol