Synthesis of DES1 inhibitors to study the sphingolipid metabolism in non-alcoholic fatty liver disease

Abstract

Evidence indicates that ceramides, and more recently dihydroceramides, are involved in several biological processes, such as sphingolipid metabolism and cell signalling. Furthermore, it is believed that they have critical roles in insulin resistance, oxidative stress and inflammation, which are pathologies associated with non-alcoholic fatty liver disease (NAFLD). Therefore, these bioactive molecules and the enzyme that regulates the conversion of ceramide into dihydroceramide (DES1) are potential therapeutic targets [1][2][3]. This project has successfully prepared two compounds for the study of their potential inhibition activity over DES1. They consisted in the preparation at larger scale of a potential therapeutic drug (N-(4-hydroxyphenyl)garcinamide, 2) to treat mice fed with a high-fat diet and a new class of inhibitors for hepatic cell cultures ((E)-Δ6 ceramides), for which a new synthetic route was developed. Concretely, the synthesized inhibitor of this class was N-((2S,3R,E)-1,3-dihydroxyoctadec-6-en-2-yl)pivaloylamide (8). These compounds were characterized by NMR and mass spectroscopy analysis