ABSTRACT
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.
Subject(s)
Polycyclic Compounds/chemical synthesis , Small Molecule Libraries/chemical synthesis , Sulfoxides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cycloaddition Reaction , Drug Discovery , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Spiro Compounds/chemical synthesis , StereoisomerismABSTRACT
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.
Subject(s)
Acid Ceramidase/metabolism , Fabry Disease/metabolism , Gaucher Disease/metabolism , Glycosphingolipids/metabolism , Acid Ceramidase/genetics , Acylation , Animals , Disease Models, Animal , Fabry Disease/genetics , Female , Gaucher Disease/genetics , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Glycosphingolipids/chemistry , HEK293 Cells , Humans , Lysosomes/metabolism , Male , Mice , Mice, Knockout , alpha-Galactosidase/genetics , alpha-Galactosidase/metabolismABSTRACT
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.