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

被引:20
作者
Maximov, Philipp Y. [1 ]
Fernandes, Daphne J. [1 ]
McDaniel, Russell E. [1 ]
Myers, Cynthia B. [2 ]
Curpan, Ramona F. [3 ]
Jordan, V. Craig [1 ]
机构
[1] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA
[2] Fox Chase Canc Ctr, Organ Synth Facil, Philadelphia, PA 19111 USA
[3] Romanian Acad, Inst Chem, Timisoara 300223, Romania
关键词
BREAST-CANCER; PROLACTIN SYNTHESIS; NONSTEROIDAL ANTIESTROGENS; HYDROXYLATED METABOLITES; TAMOXIFEN METABOLITES; ADJUVANT CHEMOTHERAPY; ACCURATE DOCKING; ALPHA; GLIDE; MODEL;
D O I
10.1021/jm500569h
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:4569 / 4583
页数:15
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