RESUMO
Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.
Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Isoxazóis/química , Isoxazóis/farmacologia , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/química , Aminoácidos/química , Aminoácidos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Ácido Glutâmico/metabolismo , Humanos , Hidrazonas/química , Hidrazonas/farmacologia , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The first thermally robust and air stable bent-sandwich chromocene complex with chromium in the +4 oxidation state has been isolated and fully characterized.
RESUMO
A series of 4-isoxazolyl-1,4-dihydropyridines (IDs) were prepared and characterized, and their interaction with the calcium channel was studied by patch clamp analysis. The structure-activity relationship (SAR) that emerges is distinct from the 4-aryldihydropyridines (DHPs), and affinity increases dramatically at higher holding potentials. Thus, among the 3'-arylisoxazolyl analogues p-Br > p-Cl >> p-F, and p-Cl > m-Cl > o-Cl >> o-MeO. Four of the analogues were examined by single-crystal X-ray diffractometry, and all were found to adopt an O-exo conformation in the solid state. The calculated barrier to rotation, however, suggests that rotation about the juncture between the heterocyclic rings is plausible under physiological conditions. A variable-temperature NMR study confirmed the computation. With Striessnig's computational sequence homologation procedure, a working hypothesis was derived from the data that explains the unique SAR for IDs.
