RESUMO
The design and synthesis of three novel polycyclic scaffolds containing sulfoximines are presented in this work, which exemplify that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory.
Assuntos
Compostos Policíclicos/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Sulfóxidos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Reação de Cicloadição , Descoberta de Drogas , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Compostos de Espiro/síntese química , EstereoisomerismoRESUMO
Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and α-galactosidase A (Fabry disease). Independent genetic and pharmacological evidence is presented pointing to an active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids. The potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects is discussed.
Assuntos
Ceramidase Ácida/metabolismo , Doença de Fabry/metabolismo , Doença de Gaucher/metabolismo , Glicoesfingolipídeos/metabolismo , Ceramidase Ácida/genética , Acilação , Animais , Modelos Animais de Doenças , Doença de Fabry/genética , Feminino , Doença de Gaucher/genética , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Glicoesfingolipídeos/química , Células HEK293 , Humanos , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Knockout , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismoRESUMO
Acid ceramidase is responsible for the ultimate step in the catabolism of (glyco)sphingolipids by hydrolysis of ceramide into sphingosine and free fatty acid. Deficiency in acid ceramidase is the molecular basis of Farber disease. Here we report the synthesis and characterization of an activity-based acid ceramidase probe.
Assuntos
Ceramidase Ácida/análise , Ceramidase Ácida/metabolismo , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Ceramidas/química , Ceramidas/metabolismo , Ativação Enzimática , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Hidrólise , Sondas Moleculares/síntese química , Estrutura Molecular , Esfingolipídeos/química , Esfingolipídeos/metabolismo , Esfingosina/química , Esfingosina/metabolismoRESUMO
Three tetrahydropyridoimidazole-type glycosidase inhibitors have been synthesized with the 3-deoxy ribo- and arabino-, and 3-deoxy-3-fluoro gluco-configurations and two of them screened for activity against α- and ß-gluco- and mannosidase enzymes. Only one substance, the 3-deoxy-3-fluoro-derivative of the gluco-configured tetrahydropyridoimidazole was found to have any activity against a single enzyme, sweet almond ß-glucosidase, and even then at a level 100-fold lower than that of the corresponding simple gluco-configured tetrahydropyridoimidazole thereby underlining the importance of the 3-hydroxy group in the key substrate-enzyme interactions.
Assuntos
Inibidores Enzimáticos/síntese química , Glucosidases/química , Glucosídeos/química , Himecromona/análogos & derivados , Imidazóis/química , Proteínas de Plantas/química , Proteínas de Saccharomyces cerevisiae/química , Ensaios Enzimáticos , Himecromona/química , Especificidade por SubstratoRESUMO
N-Acylation of furfurylamines provided 1, which on double deprotonation with LDA led to the formation of N-acyl-5-aminopenta-2,4-dienals 2 via an isomerization involving opening of the furan ring. The scope and limitations of the procedure were examined by considering the influence of substituents on the carbonyl group and also on the heterocycle moiety. The efficacy of the reaction was shown to be very dependent on the nature of these groups.
