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

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.