Further probing of the substrate specificities and inhibition of enzymes involved at an early stage of glycosylphosphatidylinositol (GPI) biosynthesis

Abstract

1- d-6- O-(2-Amino-2-deoxy-α- d-glucopyranosyl)-1- O-hexadecyl- myo-inositol ( 14), 1- d-6- O-(2-amino-2-deoxy-α- d-glucopyranosyl)- myo-inositol 1-(octadecyl phosphate) ( 18), 1- d-6- O-(2-amino-2-deoxy-β- d-glucopyranosyl)- myo-inositol 1-(1,2-di- O-hexadecanoyl- sn-glycerol 3-phosphate) ( 24), 1- d-6- O-(2-amino-2-deoxy-α- d-mannopyranosyl)- myo-inositol 1-(1,2-di- O-hexadecanoyl- sn-glycerol 3-phosphate) ( 30) and the corresponding 2-amino-2-deoxy-α- d-galactopyranosyl analogue 36 have been prepared and tested in cell-free assays as substrate analogues/inhibitors of α-(1→4)- d-mannosyltransferases that are active early on in the glycosylphosphatidylinositol (GPI) biosynthetic pathways of Trypanosoma brucei and HeLa (human) cells. The corresponding N-acetyl derivatives of these compounds were similarly tested as candidate substrate analogues/inhibitors of the N-deacetylases present in both systems. Following on from an early study, 1- l-6- O-(2-amino-2-deoxy-α- d-glucopyranosyl)-2- O-methyl- myo-inositol 1-(1,2-di- O-hexadecanoyl- sn-glycerol 3-phosphate) ( 44) was prepared and tested as an inhibitor of the trypanosomal α-(1→4)- d-mannosyltransferase. A brief summary of the biological evaluation of the various analogues is provided.