Synthesis of Inimosugars with Piperidine Core from a,b-Unsaturated Diazoketones with Z Geometry

• Grant number: 15/11793-7
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: September 01, 2015
• End date: December 31, 2015
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Antonio Carlos Bender Burtoloso
• Grantee: Meire Yasuko Kawamura
• Supervisor: Yves Genisson
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: 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.