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Design, synthesis and biological evaluation of novel selective inhibitors of the hydrolase O-GlcNAcase (OGA)

Grant number: 16/04003-2
Support type:Scholarships in Brazil - Master
Effective date (Start): June 01, 2016
Effective date (End): February 28, 2018
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Ivone Carvalho
Grantee:Michelle Ogava Igual
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The O-GlcNAcylation or O-GlcNAc modification is regulated by two importante enzimes, a glycosyltransferase, known as O-GlcNAc transferase (OGT) and a hydrolase, O-GlcNAcase (OGA). Several studies have shown the importance of O-GlcNAcylation in essential cellular process and its correlation with type 2 diabetes, Alzheimer Disease and cancer. Many inhibitors have been described so far. However, the questionings related to these compounds are due to lack of selectivity between the OGA and the enzymes beta-hexosaminidase A and beta-hexosaminidase B, which play a fundamental role recycling glycosphingolipids within the lysosomes. The results from the previous study were interesting, with the tested compounds presenting no cytotoxicity, and the compound methyl 2-[(2-phenyl)ethyl-(1H-1,2,3-triazole-4-yl)]-2-deoxi-²-D-glucopyranoside (26) had an inhibitory activity comparable to Thiamet-G, a potent inhibitor described against OGA. These preliminary results open a wider perspective in order to obtain novel derivatives more active and selective toward OGA. The novel compounds will be obtained using the synthetic route optimized in the previous study, starting from 2-amino-2-deoxy-D-glucose hydrochloride, which imply the acetylation of the hydroxyl groups of the carbohydrate and formation of glycosyl bromide donor for further glycosylation reaction with methanol. The glycosylated compound will be submitted to the diazo transfer reaction, followed by the CuAAC reaction with different alkynes. The synthesized compounds will be evaluated for cytotoxicity, O-GlcNAcylation pattern and selectivity over OGA and the beta-hexosaminidases A e B. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
IGUAL, MICHELLE O.; NUNES, PAULO S. G.; DA COSTA, RAFAEL M.; MANTOANI, SUSIMAIRE P.; TOSTES, RITA C.; CARVALHO, IVONE. Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA). Carbohydrate Research, v. 471, p. 43-55, JAN 1 2019. Web of Science Citations: 2.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
. Design, synthesis and biological evaluation of novel selective inhibitors of the hidrolase O-GlcNAcase (OGA). 2018. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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