RESUMO
Environment-sensitive binding of anions to synthetic receptors is important for the functional mimicry of ion channels. We describe new squaramide-based chloride ion receptors whose anion binding cavity can be opened and closed by using carbonyl groups as valves. In nonpolar solvents, the carbonyls preclude chloride binding via intramolecular hydrogen bonding with the squaramide NHs. In polar solvents, disruption of the intramolecular hydrogen bonds reorients the carbonyl groups and opens the anion-binding cavity.
Assuntos
Amidas/química , Cloretos/química , Ciclobutanos/química , Materiais Biomiméticos/química , Canais de Cloreto/química , Canais Iônicos/químicaRESUMO
The actions of estrogens are mediated through the two estrogen receptors, ERalpha and ERbeta. Compounds that interact selectively with ERalpha or ERbeta are of interest because they could be used to explore the biological roles of these ER subtypes and they might be interesting estrogen pharmaceuticals. In a new approach to develop ER subtype-selective ligands, we have embellished the 1,1-diarylethylene motif, common to many nonsteroidal estrogens, with various bridged bicyclic or tricyclic cores, including ones based on bicyclo[3.3.1]nonane, bicyclo[2.2.1]heptane, and selected bi- and tricyclic terpenoids. This design leads to three-dimensional ER ligands of unusual structure that we have used to probe the size and shape of the ligand binding pocket of ERalpha and ERbeta. Many of these compounds have high binding affinities, with the best having a bicyclo[3.3.1]nonane core and binding 3-5 times better than estradiol to both ER subtypes. Some of the compounds show significant affinity selectivity in favor of ERbeta (4- to 5-fold), and in cell-based assays for transcriptional activity most are partial agonists on ERalpha and full antagonists on ERbeta.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Receptores de Estrogênio/metabolismo , Ligação Competitiva , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Humanos , Ligantes , Modelos Moleculares , Ensaio Radioligante , Receptores de Estrogênio/agonistas , Receptores de Estrogênio/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
[structure: see text] To examine the possibility of using squaric acid as a scaffold for organizing phenyl rings in a cofacial orientation, we undertook an investigation of the conformational preferences of secondary and tertiary N-phenylsquaramides. In secondary squaramides, the extended ZZ conformation is preferred, while in the N-methyl derivative, the folded EE conformation with cofacial phenyl rings is preferred. This conformational switch is likely driven by a combination of steric and electronic factors.
RESUMO
A new design strategy is described for chloride ion sensors based on suppression of excited state intramolecular proton transfer in squaramides as a fluorescence "turn on" mechanism.
Assuntos
Amidas/química , Cloretos/química , Prótons , Fluorescência , Estrutura MolecularRESUMO
Tertiary aryl squaramides were synthesized by using copper catalyzed C-N bond-formation with L-proline as the ligand. Symmetrical diaryl squaramides could be prepared in a one-pot reaction by using excess aryl bromide with varying yields. Unsymmetrical derivatives were prepared by sequential arylation. Yields of the diarylated products were highly sensitive to steric effects.
Assuntos
Amidas/química , Cobre/química , Ligantes , Estrutura MolecularRESUMO
Three novel structural motifs based on a bicyclo [3.3.1]nonane template were examined as new ligands for estrogen receptor (ER). Type III compounds emerged as the most promising leads for developing high-affinity ER ligands, but they showed little selectivity for either ER subtype. Type II compounds, on the other hand, despite their lower affinity, exhibited significant ERbeta binding selectivity.
Assuntos
Alcanos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Receptores de Estrogênio/metabolismo , Alcanos/síntese química , Alcanos/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Ciclofenil/metabolismo , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Indicadores e Reagentes , Cinética , Ligantes , Modelos Moleculares , Estrutura Molecular , Ensaio Radioligante , Receptores de Estrogênio/efeitos dos fármacos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Equol is a metabolite produced in vivo from the soy phytoestrogen daidzein by the action of gut microflora. It is known to be estrogenic, so human exposure to equol could have significant biological effects. Equol is a chiral molecule that can exist as the enantiomers R-equol and S-equol. To study the biological activity of racemic (+/-)-equol, as well as that of its pure enantiomers, we developed an efficient and convenient method to prepare (+/-)-equol from available isoflavanoid precursors. Furthermore, we optimized a method to separate the enantiomers of equol by chiral HPLC, and we studied for the first time, the activities of the enantiomers on the two estrogen receptors, ERalpha and ERbeta. In binding assays, S-equol has a high binding affinity, preferential for ERbeta (K(i)[ERbeta]=16 nM; beta/alpha=13 fold), that is comparable to that of genistein (K(i)[ERbeta]=6.7 nM; beta/alpha=16), whereas R-equol binds more weakly and with a preference for ERalpha (K(i)[ERalpha]=50 nM; beta/alpha=0.29). All equol isomers have higher affinity for both ERs than does the biosynthetic precursor daidzein. The availability and the in vitro characterization of the equol enantiomers should enable their biological effects to be studied in detail.