N-alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen

18Citations
Citations of this article
7Readers
Mendeley users who have this article in their library.
Get full text

Abstract

The preparation of a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1Z-alkoxyphenyl group in tamoxifen has been replaced by a N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-N,N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERα) affinity assay. Several compounds exhibited binding affinities 2-5-fold lower than tamoxifen. Dose-response experiments with six selected compounds were carried out using two different human breast cancer cell lines, MCF-7 and the tamoxifen resistant cell line MCF-/TAMR-1. Both cell lines exhibited growth inhibition upon treatment with the tamoxifen analogues. Co-treatment of the cells, with estradiol and the individual compounds, were also performed. The results indicated that the observed growth inhibitory effect was mediated by the ERα. Analogues of the potent antiestrogen 4-hydroxytamoxifen (4-OHT) were synthesised where the 1E-4-hydroxyphenyl was replaced by a 1-hydroxypyrazol-4-yl group. However, modest growth inhibition of MCF-7 cells was observed upon treatment with these analogues. In contrast, 1Z-, 2Z-ringclosed tamoxifen analogue (59) was shown to possess antiproliferative effects on MCF-7 and MCF-/TAMR-1 cells in lower doses than tamoxifen. © 2003 Elsevier Science Ltd. All rights reserved.

Cite

CITATION STYLE

APA

Wenckens, M., Jakobsen, P., Vedsø, P., Huusfeldt, P. O., Gissel, B., Barfoed, M., … Begtrup, M. (2003). N-alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen. Bioorganic and Medicinal Chemistry, 11(8), 1883–1899. https://doi.org/10.1016/S0968-0896(02)00566-7

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free