Synthesis of bioisosteres of N-acetyl-glucosamine as potential inhibitors of O-GlcNAcase hydrolase

• Grant number: 14/25960-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2015
• End date: December 31, 2015
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ivone Carvalho
• Grantee: Michelle Ogava Igual
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The glycosylation of nuclear and cytoplasmic proteins with one unit of N-acetylglucosamine covalently bond at serine and threonine residues via O-²-Glyosidic linkage is known as O-GlcNAc modification. Two enzymes are involved in this process: a glycosyltransferase, referred to as O-GlcNAc transferase (OGT), which transfers molecules of N-acetylglucosamine, via Uridine 5'-diphosphate-acetylglucosamine (UDP- GlcNAc), and a hydrolase called O-GlcNAcase (OGA), that dynamically removes those groups. Several studies have shown the importance of O-GlcNAcylation in essential cellular process and its correlation with type 2 diabetes, Alzheimer's Disease and cancer. Thus, small molecules that are able to inhibit OGA are useful strategy in the treatment of those chronic-degenerative diseases. Many inhibitors have been described so far. However, the questionings related to these compounds are due to the lack of selectivity between the OGA and the enzymes ²-hexosaminidase A (Hex A) and ²-hexosaminidase B (HEX B). Therefore, the selection of higher selectivity prototypes towards the active site of OGA will be made from previous studies of Molecular Docking to direct the synthesis of new potential inhibitors of the enzyme OGA. The proposed compounds will be derived from glucosamine hydrochloride, containing different groups at C-2 linked with a triazole ring, using low cost and easily performed strategies. (AU)