Synthesis of Biologically Relevant Sphingolipid Analogues

This Ph.D. study constitutes part of an extensive project dealing with the synthesis of biologically relevant sphingoid and ceramide analogues. In this context, we effected the synthesis of two different classes of sphingolipid analogues. In a first part, we aimed at the synthesis of hybrid PDMP analogues, based both on PDMP and styryl analogues of natural ceramide. Since preliminary synthetic approaches based on a mono-protective strategy resulted in undesired cyclisation products, a double-protective strategy was devised in which the secondary alcohol and the tert-Boc protected amine were locked in an oxazolidine ring. Hence, the desired E-styryl PDMP analogues have been synthesised in 16 steps starting from D-serine. The synthetic route was developed such that future introduction of different aryl groups is straightforward. Throughout the synthetic coarse, we gained access to a number of structural analogues, which provided more insight into the structure-activity relationship of this class of compounds. Biological evaluation, both in vitro on rat liver Golgi extracts as in vivo on HEK-293 and COS-7 cells revealed two lead compounds with comparable inhibitory potency as PDMP, which could be elaborated to more potent inhibitors. In a second part, we aimed at the synthesis of a new class of homoceramides, named N-homoceramides, which contain an extra methylene-spacer between the N-acyl chain and C2 of the sphingoid backbone. To this aim, we evaluated the introduction of branching by use of a cyano group, both in a sugar approach as in regioselective epoxide opening. Since these experiments failed to provide a reliable means for introduction of branching, we opted to introduce an extra methylene spacer by use of 1,3-dithiane. Hence, the desired N-homo(dihydro)ceramides have been synthesized in 20 steps starting from D-ascorbic acid, a common food preservative. Key reaction in this synthetic approach was a fully regioselective epoxide opening with lithium 1,3-dithiane. In addition, a fully stereoselective Grignard reaction gave access to D-ribo-N-homophytoceramide.

Author dc:creator

• Hillaert, Ulrik

Contributors dc:contributor

• Van Calenbergh, S

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

und

Identifier

https://biblio.ugent.be/publication/470194
http://doi.org/1854/3542
https://biblio.ugent.be/publication/470194/file/1877360

OAI identifier oai:identifier

oai:archive.ugent.be:470194