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J Med Chem. 2014 Jun 12;57(11):4569-83. doi: 10.1021/jm500569h. Epub 2014 May 22.

Influence of the length and positioning of the antiestrogenic side chain of endoxifen and 4-hydroxytamoxifen on gene activation and growth of estrogen receptor positive cancer cells.

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1
Lombardi Comprehensive Cancer Center, Georgetown University , 3970 Reservoir Road NW, Research Building, Suite E501, Washington, D.C. 20057, United States.

Abstract

Tamoxifen has biologically active metabolites: 4-hydroxytamoxifen (4OHT) and endoxifen. The E-isomers are not stable in solution as Z-isomerization occurs. We have synthesized fixed ring (FR) analogues of 4OHT and endoxifen as well as FR E and Z isomers with methoxy and ethoxy side chains. Pharmacologic properties were documented in the MCF-7 cell line, and prolactin synthesis was assessed in GH3 rat pituitary tumor cells. The FR Z-isomers of 4OHT and endoxifen were equivalent to 4OHT and endoxifen. Other test compounds used possessed partial estrogenic activity. The E-isomers of FR 4OHT and endoxifen had no estrogenic activity at therapeutic serum concentrations. None of the newly synthesized compounds were able to down-regulate ER levels. Molecular modeling demonstrated that some compounds would each create a best fit with a novel agonist conformation of the ER. The results demonstrate modulation by the ER complex of cell replication or gene transcription in cancer.

PMID:
24805199
PMCID:
PMC4059272
DOI:
10.1021/jm500569h
[Indexed for MEDLINE]
Free PMC Article
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