Synthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan

Abstract

Summary Mycobacterium tuberculosis, the causitive agent of tuberculosis (TB), possesses a complex cell wall containing mannose-rich glycophospholids termed phosphatidylinositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM). These glycophospholipids play important roles in cell wall function and host–pathogen interactions. Synthetic PIM/LM/LAM substructures are useful biochemical tools to delineate and dissect the fine details of mannose glycophospholipid biosynthesis and their interactions with host cells. We report the efficient synthesis of a series of azidooctyl di- and trimannosides possessing the following glycan structures: α-Man-1,6-α-Man, α-Man-1,6-α-Man-1,6-α-Man, α-Man-1,2-α-Man-1,6-α-Man and 2,6-di-(α-Man)-α-Man. The synthesis includes the use of non-benzyl protecting groups compatible with the azido group and preparation of the branched trisaccharide structure 2,6-di-(α-Man)-α-Man through a double glycosylation of a 3,4-butanediacetal-protected mannoside. The azidooctyl groups of these synthetic mannans were elaborated to fluorescent glycoconjugates and squaric ester derivatives useful for further conjugation studies.

Cellular and Humoral Mechanisms Involved in the Control of Tuberculosis

“…The control of Mtb infection begins with the recognition of mycobacterial structural components of the cell wall such as mycolic acids, peptidoglycans, arabinogalactins, phosphatidyl-myo-inositol mannosides (PIM), mannose-capped lipoarabinomannan (Man-LAM), lipomannan, and mannoglycoproteins [ 31 , 32 ]. The recognition of conserved molecular patterns is possible through pattern recognition receptors (PRR), among them the best known are the TLRs, nucleotide-binding oligomerization domain-like receptor (NLR), C-type lectins, and scavenger and complement receptors [ 33 – 36 ].…”

Expeditious Synthesis of Orthogonally Protected Saccharides through Consecutive Protection/Glycosylation Steps

“…In N-glycans, for instance, d-mannose is usually attached to either another d-mannose or N-acetylglucosamine via a1,2-, a1,3-, a1,6-, and b1,4-linkages. [1] Many bioactive glycoconjugates also contain multiple mannose residues in correlation with their physiological activities, such as GPI anchors, [2] fungal cell wall mannans, [3] and high affinity sugar ligands of concanavalin A [4] and cyanovirin N. [5] Mycobacterium tuberculosis, the main cause of tuberculosis, possesses mannose-rich glycophospholipids, which contain the 1,6-linear trimannosaccharide, to effectively avoid immune surveillance. [6] Mannose is known to easily form branched structures.…”

Synthesis of a Glycosylphosphatidylinositol (GPI) Fragment as a Potential Substrate for Mannoprotein Transglycosidases

“…22 Treatment of thiomannoside 5 with benzoic acid, DIAD, and Ph 3 P in dry THF afforded the primary benzoate 10 (Scheme 3). 23 Selective protection of the 3-and 4-positions was achieved upon reaction with butane-2,3-dione, trimethyl orthoformate, and a catalytic amount of TsOH, affording the acceptor 7, 24 corresponding to fragment C. The trichloroacetamidate donor 13, corresponding to fragment D, was readily obtained by anomeric deprotection of mannose pentabenzoate (11), followed by reaction of the resulting hemiacetal 12 with Cl 3 CCN and DBU (Scheme 3).…”