RESUMO
Competitive inhibitors of either α-galactosidase (α-Gal) or ß-galactosidase (ß-Gal) with high affinity and selectivity have been accessed by exploiting aglycone interactions with conformationally locked sp(2)-iminosugars. Selected compounds were profiled as potent pharmacological chaperones for mutant lysosomal α- and ß-Gal associated with Fabry disease and GM(1) gangliosidosis.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Doença de Fabry/tratamento farmacológico , Gangliosidose GM1/tratamento farmacológico , alfa-Galactosidase/antagonistas & inibidores , beta-Galactosidase/antagonistas & inibidores , Doença de Fabry/enzimologia , Doença de Fabry/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Gangliosidose GM1/enzimologia , Gangliosidose GM1/genética , Humanos , Imino Açúcares/química , Modelos Moleculares , Mutação , alfa-Galactosidase/genética , beta-Galactosidase/genéticaRESUMO
A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B(2) from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors is presented. The methodology relies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further undergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepared and screened against several glycosidases in comparison with xylonojirimycin-type piperidine analogues. Interestingly, strong and highly specific inhibition of bovine liver beta-glucosidase was observed for 6-oxacalystegine B(2) analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.
Assuntos
Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Nortropanos/síntese química , Animais , Ligação Competitiva , Sequência de Carboidratos , Bovinos , Café/enzimologia , Inibidores de Glicosídeo Hidrolases , Fígado/enzimologia , Dados de Sequência Molecular , Nortropanos/farmacologia , Prunus/enzimologia , Saccharomyces cerevisiae/enzimologia , Alcaloides de Solanáceas , Estereoisomerismo , beta-Glucosidase/antagonistas & inibidoresRESUMO
A series of aminoketalic castanospermine analogues incorporating a stereoelectronically anchored axial hydroxy group at the pseudoanomeric stereocenter (C-5) have been synthesized to satisfy the need for glucosidase inhibitors that are highly selective for alpha-glucosidases. The polyhydroxylated bicyclic system was built from readily available hexofuranose derivatives through a synthetic scheme that involved (i) the construction of a five-membered cyclic (thio)carbamate or (thio)urea moiety at the nonreducing end and (ii) the intramolecular nucleophilic addition of the heterocyclic thiocarbamic nitrogen atom to the masked aldehyde group of the monosaccharide. A biological screening of the resulting reducing 2-oxa- and 2-azaindolizidines against several glycosidase enzymes is reported.
