RESUMO
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a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1Z-alkoxyphenyl group in tamoxifen has been replaced by a N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2Z-position using sequential Suzuki cross coupling of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.
Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Tamoxifeno/análogos & derivados , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Estradiol/farmacologia , Receptor alfa de Estrogênio , Feminino , Humanos , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Células Tumorais CultivadasRESUMO
Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.5-1.8 nM).
Assuntos
Cromanos/síntese química , Receptores de Estrogênio/agonistas , Animais , Ligação Competitiva , Cromanos/química , Cromanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Endométrio/citologia , Endométrio/efeitos dos fármacos , Estradiol/metabolismo , Feminino , Coelhos , Relação Estrutura-Atividade , Compostos de Enxofre/síntese química , Compostos de Enxofre/química , Compostos de Enxofre/farmacologiaRESUMO
The syntheses and in vitro pharmacological evaluation of a number of cis-3,4-diaryl-hydroxy-chromanes are reported, along with the results of a thorough in vivo profiling of the tissue-selective estrogen partial-agonist NNC 45-0781 [3, (-)-(3S,4R)-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane]. These studies showed that NNC 45-0781 is a very promising candidate for the prevention of post-menopausal osteoporosis, and the treatment of other health issues related to the loss of endogenous estrogen production.