Synthesis and biological evaluation of analogues of a glycosyltransferase inhibitor

Abstract

Glycosphingolipids (GSLs) have been found to be involved in a myriad of cellular function, including the following: cell-cell communication, cell adhesion and proliferation, neuronal growth and repair, immune response and tumor progression (metastasis). To study the cellular effects of GSL depletion, Radin developed the first known inhibitors of the enzyme responsible for the initial glycosylation of the lipid portion (ceramide) of the glycosphingolipid. This inhibitor, PDMP (1-phenyl 2-decanoyl amino 3-morpholino 1-propanol), not only suppresses the initial glycosylation, but also inhibits the formation of all preceding glycosphingolipids and causes the accumulation of ceramide, an active participant in cellular apoptosis (or programmed cell death). Using a developed procedure, PDMP analogues with truncations about the aromatic region were synthesized. Aromatic PDMP analogues were more potent than the lead compound when tested against isolated embryonic cells from the Manduca sexta. Later procedures developed allowed for the manufacturing of head group analogue, which allowed for the generation of a water-soluble PDMP analogue. A new synthetic protocol, using a commercially available advanced intermediate, permitted the production of enantiomerically pure PDMP in five steps with an overall yield of 50%. As these compounds gain more medicinal attention, we hope to use PDMP and analogues, combined with the Manduca sexta as a model system, to gain a greater understanding of GSL functionality and cellular malfunctions---including cancer metastasis.