RESUMO
Fluorinated and conformationally fixed derivatives of L-homoDMDP, i.e., 2,5-dideoxy-2,5-imino-DL-glycero-L-manno-heptitol, have been synthesized from d-xylose-derived cyclic nitrone 10 with oxazolidinone 19 or 28 and oxazinanone 22 or 32 as key intermediates. An evaluation of glycosidase inhibition showed replacement of the C-6 hydroxyl groups with fluoride in L-homoDMDP and its C-6 epimer did not have a significant influence on α-glucosidase inhibition by these iminosugars, while replacement of an amino group with a cyclic carbamate group in most conformationally fixed derivatives led to a sharp decrease in the level of glycosidase inhibition, revealing the importance of the free amino group in interaction of enzymes with these molecules.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Imino Açúcares/química , Oxazolidinonas/síntese química , alfa-Glucosidases/química , Halogenação , Imino Açúcares/síntese química , Conformação Molecular , Estrutura Molecular , Oxazolidinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Australine (1), 7-epi-australine (2), and their C-7-fluorinated derivatives 4 and 5 have been synthesized efficiently from D-arabinose-derived cyclic nitrone 11. Fluorination at the C-7 position enhanced the inhibition against A. niger α-glucosidase, and this constitutes the first example of fluorination substitution for a hydroxyl increasing the inhibition of any glycosidases. The enantiomers synthesized from nitrone ent-11 showed no inhibition of the corresponding enzymes.
Assuntos
Glicosídeo Hidrolases/antagonistas & inibidores , Hidrocarbonetos Fluorados/síntese química , Alcaloides de Pirrolizidina/síntese química , Arabinose/análogos & derivados , Arabinose/química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/efeitos dos fármacos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Estrutura Molecular , Óxidos de Nitrogênio/química , Alcaloides de Pirrolizidina/química , Estereoisomerismo , Relação Estrutura-Atividade , alfa-GlucosidasesRESUMO
The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by-side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucuronatos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/química , Imino Açúcares/síntese química , Imino Açúcares/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Primary amines with either 3,5-di-O-ditriflates of α-furanosides or 2,4-di-O-triflates of ß-pyranosides form bicyclic azetidines in high yield.
Assuntos
Aminas/química , Azetidinas/síntese química , Glucose/química , Imino Açúcares/síntese química , Mesilatos/química , Azetidinas/química , Ciclização , Imino Açúcares/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of neoglycoconjugates derived from deoxynojirimycin has been prepared by click connection with functionalised adamantanes. They have been assayed as glycosidase inhibitors, as inhibitors of the glycoenzymes relevant to the treatment of Gaucher disease, as well as correctors of the defective ion-transport protein involved in cystic fibrosis. We have demonstrated that it is possible to selectively either strongly inhibit ER-α-glucosidases and ceramide glucosyltransferase or restore the activity of CFTR in CF-KM4 cells by varying the length of the alkyl chain linking DNJ and adamantane.
