The Chemical Synthesis of Bioactive Glycosylphosphatidylinositols from Trypanosoma cruzi Containing an Unsaturated Fatty Acid in the Lipid

Abstract

Protection strategy: Glycosylphosphatidylinositols (GPIs) from the Trypanosoma cruzi parasite (a causative agent of Chagas' disease) that contain an unsaturated fatty acid in the lipid moiety (see partial structure of 1, R=(CH2)7CHCH(CH2)7CH3, and 2, R=(CH2)7CHCHCH2CHCH(CH2)4CH3) were prepared by a strategy that employs non‐benzyl‐type protecting groups. The synthetic GPIs show similar biological activity to their natural counterparts.

Total synthesis of the fully lipidated glycosylphosphatidylinositol (GPI) anchor of malarial parasite Plasmodium falciparum

“…Arguably, the most demanding aspect of the GPI synthesis has been to access suitably protected glucosamine-inositol block requiring optically pure protected D-myo-inositol acceptor and 2-azido-2-deoxyglucosyl donor. This has mainly been accomplished by previous workers [8][9][10][11][12] either by the a priori resolution of bis-cyclohexylidene-myo-inositols by chiral auxiliaries and enzymes or through a multi-step synthesis from D-glucose by the Ferrier reaction.…”

“…Although a number of approaches have been reported [8][9][10][11][12] by various leading groups for the synthesis of GPI anchors of various parasitic species, including our own approach, 13 the GPI molecules of the malarial parasite present increasing challenges due to the presence of a third fatty acid group at the 2-position of the myo-Dinositol residue. For this reason, so far only one total synthesis of fully lipidated Pf-GPI has been reported (Seeberger et al).…”

Glycosylphosphatidylinositols of Protozoan Parasites

“…To date some protozoan GPIs have been synthesized using different glycosylation and protecting group strategies by either linear or convergent means, including GPI anchors of T. brucei (44,45), T. cruzi (46,47), P. falciparum (48)(49)(50) and T. gondii (51,52). In general, all syntheses began with glycan assembly, followed by the installation of phosphate groups and final deprotection.…”

Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

“…The azido moiety can then be reduced under a variety of reaction conditions amongst which are catalytic hydrogenation (H 2 , Pd/C), 52-54 treatment with 1,3-propanedithiol, 55 Staudinger ligation (Ph 3 P in THF/ H 2 O), 56,57 or Birch reduction (Na/liquid NH 3 ). 58,59 The free amine can then be converted into acetamido or other NHR or NR 2 derivatives by simple protecting group chemistry.…”