RESUMO
A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver ß-glucosidase/ß-galactosidase and specific inhibition of human ß-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location. Molecular dynamics simulations highlighted the paramount importance of an optimal orientation of the hydrophobic substituent to warrant efficient non-glycone interactions, which are critical for the binding affinity. The results provide a rationale for the strong decrease of the inhibition potency of APP compounds on going from neutral to acidic pH. The best candidate was found to behave as pharmacological chaperone in Gaucher fibroblasts with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound Ambroxol.
Assuntos
Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Doença de Gaucher/patologia , Chaperonas Moleculares/farmacologia , Monossacarídeos/farmacologia , Animais , Bovinos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glucosilceramidase/antagonistas & inibidores , Glicosídeos , Humanos , Fígado/enzimologia , Modelos Moleculares , Chaperonas Moleculares/síntese química , Chaperonas Moleculares/química , Conformação Molecular , Simulação de Dinâmica Molecular , Monossacarídeos/síntese química , Monossacarídeos/química , Relação Estrutura-Atividade , beta-Galactosidase/antagonistas & inibidores , beta-Glucosidase/antagonistas & inibidoresRESUMO
[structure: see text]. In this paper we describe a highly regioselective ring-opening metathesis-cross metathesis (ROM-CM) process between methyl N-Boc-7-azabicyclo[2.2.1]hept-2-en-1-carboxylate, a bridgehead-substituted 7-azanorbornene system, and electron-poor olefins. The reaction opens the way to the synthesis of interesting alpha-amino diacids and pyrrolizinone derivatives that incorporate quaternary stereocenters.
RESUMO
This work is connected with the epibatidine field and describes the synthesis of several analogues of compounds that present affinity for nicotinic acetylcholine receptors, such as 3-[1-methyl-2-(S)-pyrrolidinylmethoxy]pyridine (A-84543). These analogues bear a 3-pyridyl ether substituent at the bridgehead carbon of the azabicyclo[2.2.n]alkane system. Particularly, in the case of the 1-substituted 2-azabicyclo[2.2.2]octane system, a new synthetic route has been developed, which involves the synthesis of a novel rigid sulfamidate that allows the straightforward introduction of nucleophiles.
Assuntos
Alcanos/síntese química , Compostos Aza/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos com Pontes/síntese química , Agonistas Nicotínicos/química , Piridinas/química , Alcanos/química , Compostos Aza/química , Compostos Bicíclicos com Pontes/químicaRESUMO
An efficient and easily applicable method for the synthesis of a variety of hydroxy-alpha-amino acids analogues of serine and phenylalanine has been established. The method involves the stereoselective intramolecular conjugate addition of the benzamide group to cyclohexenone promoted by Lewis acid. Subsequent transformations of functional groups provide the conformationally constrained 2-hydroxy- and 2,4-dihydroxy-6-phenylcyclohexane-alpha-amino acids.
