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Synthesis of Inimosugars with piperidine core from a,b-unsaturated diazoketones with Z geometry

Grant number: 15/11793-7
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): September 01, 2015
Effective date (End): December 31, 2015
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Antonio Carlos Bender Burtoloso
Grantee:Meire Yasuko Kawamura
Supervisor abroad: Yves Genisson
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Local de pesquisa : Université Paul Sabatier - Toulouse III, France  
Associated to the scholarship:13/26399-7 - The use of a,b-unsaturated diazoketones with Z geometry in the direct construction of functionalized indolizidine skeletons. application in the synthesis of Dehydrodemethylpumiliotoxins, BP.MS

Abstract

This project aims at the use of a,b-unsaturated diazoketones with the Z geometry, developed in our group, to the synthesis of iminosugars with piperidine cores. This small organic molecules will be applied to demonstrate the relevance of therapeutic strategy SRT (Substrate Reduction Therapy) against Niemann-Pick disease (NPD), defined by the pathological lysosomal accumulation of sphingomylin (SM), belongs to a Family of rare inherited metabolic disorders referred to as "lysosomalstorage diseases" (LSDs). There are three distinct phenotypes (A-C) of NPD, in type A and B the inability of the mutante acid sphingomyelinase (ASM) to hydrolysis this substrate at a normal rate cause storage of SM within the lysosome. NPD type C is a non-ASM-deficient form of the disease. The develop of novel small molecule inhibitors of the cellular SM production will prevent SM accumulation in ASM-deficient NPD. Among the three protein that inhibit biosynthesis of SM, Cer transfer protein (CERT) was selected. Finally, six-membered inimosugars with aliphatic chains were not chosen by chance, earlier studies have shown a series of Cer (de)glucosylation inhibitors with these characteristics.