期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 11, 页码 4569-4583出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500569h
关键词
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资金
- Department of Defense Breast Program Center of Excellence [W81XWH-06-1-0590]
- Susan G. Komen for the Cure Foundation [SAC 100009]
- Lombardi Comprehensive Cancer Center Support Grant [NIH P30 CA051008]
- UEFISCU-CNCSIS [174/2010]
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.
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