RESUMEN
Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.
Asunto(s)
Ácidos Dicarboxílicos/síntesis química , Ácidos Dicarboxílicos/metabolismo , Pirazoles/síntesis química , Pirazoles/metabolismo , Receptores AMPA/metabolismo , Animales , Calcio/metabolismo , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Ácidos Dicarboxílicos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pirazoles/farmacología , Ratas , Receptores AMPA/efectos de los fármacos , EstereoisomerismoRESUMEN
N1-substituted bicyclic pyrazole amino acids (S)-9a-9c and (R)-9a-9c, which are conformationally constrained analogues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested for activity at ionotropic and metabotropic glutamate receptors. Some of them turned out to be selective for the NMDA receptors, where they behaved as weak antagonists. The biological activity is mainly due to the interaction with the glutamate binding site, and not with the glycine co-agonist site.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Receptores de Glutamato/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/metabolismo , Estructura Molecular , Receptores de Glutamato/químicaRESUMEN
The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.