title: N-Alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen.
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a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1Z-alkoxyphenyl group in tamoxifen has been replaced by a N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2Z-position using sequential Suzuki cross coupling of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 (ERalpha) 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-/TAM(R)-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 ERalpha. 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-/TAM(R)-1 cells in lower doses than tamoxifen.
authors.affiliation: Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Wenckens
authors.forename: Palle
authors.initials: P
authors.lastname: Jakobsen
authors.forename: Per
authors.initials: P
authors.lastname: Vedsø
authors.forename: Per Olaf
authors.initials: PO
authors.lastname: Huusfeldt
authors.forename: Birgitte
authors.initials: B
authors.lastname: Gissel
authors.forename: Marianne
authors.initials: M
authors.lastname: Barfoed
authors.forename: Bettina
authors.initials: B
authors.lastname: Lundin Brockdorff
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.forename: Mikael
authors.initials: M
authors.lastname: Begtrup
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001555:Benzene Derivatives; D047628:Estrogen Receptor alpha; D011720:Pyrazoles; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol