RESUMO
An efficient and mild method to couple aryl bromides and activated non-allylic alcohols in a Heck reaction with tandem isomerization to selectively afford high yields of 1,5-diarylalkan-1-ones has been developed. Mechanistic insight was gained through NMR studies of products derived from deuterium-labeled intermediates.
Assuntos
Álcoois Benzílicos/química , Brometos/química , Paládio/química , Catálise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Receptor beta de Estrogênio/agonistas , Naftalenos/síntese química , Naftóis/síntese química , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Receptor beta de Estrogênio/química , Feminino , Genisteína/química , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ligantes , Masculino , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacologia , Naftóis/química , Naftóis/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Útero/anatomia & histologia , Útero/efeitos dos fármacosRESUMO
A series of biphenyl carbaldehyde oximes (6) was prepared and shown to have significant selectivity for the estrogen receptor-beta (ERbeta). The exploitation of the oxime moiety as a hydrogen bond donating group, which mimicked the C-ring of genistein makes these compounds unique. Molecular modeling studies showed the oxime moiety hydrogen bonding to the histidine residue, which was supported by the structure-activity relationships. The most potent compounds in this study had IC50 values in a radioligand binding assay of between 8-35 nM. Among the most selective compounds were 6i and 6s (49- and 31-fold ERbeta selective, respectively).
