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1.
Org Biomol Chem ; 13(23): 6598-610, 2015 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-25986781

RESUMO

As part of an ongoing project aimed at developing vaccine candidates against Cryptococcus neoformans the preparation of tri- and tetrasaccharide thioglycoside building blocks, to be used in construction of structurally defined part structures of C. neoformans GXM capsular polysaccharide, was investigated. Using a naphthalenylmethyl (NAP) ether as a temporary protecting group and trichloroacetimidate donors in optimized glycosylations the target building blocks, ethyl 6-O-acetyl-2,4-di-O-benzyl-3-O-(2-naphthalenylmethyl)-α-D-mannopyranosyl-(1→3)-[2,3,4-tri-O-benzyl-ß-D-xylopyranosyl-(1→2)]-4,6-di-O-benzyl-1-thio-α-D-mannopyranoside (16) and ethyl 2,3,4-tri-O-benzyl-ß-D-xylopyranosyl-(1→2)-4,6-di-O-benzyl-3-O-(2-naphthalenylmethyl)-α-D-mannopyranosyl-(1→3)-[2,3,4-tri-O-benzyl-ß-D-xylopyra-nosyl-(1→2)]-6-O-acetyl-4-O-benzyl-1-thio-α-D-mannopyranoside (21), were efficiently prepared. These synthesized thiosaccharide building blocks were then used as donors in high-yielding (~90%) DMTST promoted glycosylations to a spacer-containing acceptor to, after deprotection, afford GXM polysaccharide part structures ready for protein conjugation to give vaccine candidates. Also, the NAP groups in the building blocks were removed to obtain tri- and tetrasaccharide acceptors suitable for further elongation towards larger thiosaccharide building blocks.


Assuntos
Cryptococcus neoformans/química , Polissacarídeos Fúngicos/química , Oligossacarídeos/síntese química , Xilose/química , Acetamidas/química , Sequência de Carboidratos , Técnicas de Química Sintética , Cloroacetatos/química , Glicosilação , Dados de Sequência Molecular , Oligossacarídeos/química , Tioglicosídeos/química
2.
Chem Sci ; 11(34): 9209-9217, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34123169

RESUMO

A convergent synthetic strategy to Cryptococcus neoformans glucuronoxylomannan (GXM) capsular polysaccharide part structures was developed based on di-, tri-, tetra-, penta- and hexasaccharide thioglycoside building blocks. The approach permitted the synthesis of a library of spacer-containing serotype A and D related GXM oligosaccharide structures, ranging from di- to octadecasaccharides. Ten deprotected GXM compounds (mono- to decasaccharide) were printed onto microarray plates and screened with seventeen mouse monoclonal antibodies (mAbs) to GXM. For the first time a GXM oligosaccharide structure (a serotype A decasaccharide), capable of being recognized by neutralizing forms of these GXM-specific mAbs, has been identified, offering insight into the binding epitopes of a range of protective monoclonal antibodies and furthering our efforts to develop semi-synthetic conjugate vaccine candidates against C. neoformans.

3.
ChemistryOpen ; 4(6): 729-39, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27308199

RESUMO

As part of an ongoing project aimed at identifying protective capsular polysaccharide epitopes for the development of vaccine candidates against the fungal pathogen Cryptococcus neoformans, the synthesis and glycosylation properties of a naphthalenylmethyl (NAP) orthogonally protected trisaccharide thioglycoside, a common building block for construction of serotype B and C capsular polysaccharide structures, were investigated. Ethyl (benzyl 2,3,4-tri-O-benzyl-ß-d-glucopyranosyl- uronate)-(1→2)-[2,3,4-tri-O-benzyl-ß-d-xylopyranosyl-(1→4)]-6-O-benzyl-3-O-(2-naphthalenylmethyl)-1-thio-α-d-mannopyranoside was prepared and used both as a donor and an acceptor in glycosylation reactions to obtain spacer equipped hexa- and heptasaccharide structures suitable either for continued elongation or for deprotection and printing onto a glycan array or conjugation to a carrier protein. The glycosylation reactions proceeded with high yields and α-selectivity, proving the viability of the building block approach also for construction of 4-O-xylosyl-containing C. neoformans CPS structures.

4.
Carbohydr Res ; 389: 57-65, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24612865

RESUMO

In a project targeting the synthesis of large oligosaccharide structures corresponding to the Cryptococcus neoformans GXM capsular polysaccharide, an easy access to thiodisaccharide building blocks comprising a ß-linked glucuronic acid moiety and a 6-O-acetyl group was required. Several pathways to such building blocks have been investigated, addressing the problem of constructing a ß-linked glucuronic acid residue protected with groups that are orthogonal to a primary acetyl group. Two efficient routes have been developed, one using benzoylated glucosyl donors to form the ß-linkage followed by a change of protecting groups to benzyls and subsequent introduction of the carboxyl function and the acetyl group. The second route explored the possibility to achieve ß-selectivity using glucuronyl donors without acyl protecting groups. BF3-etherate promoted glycosylations with benzyl (2,3,4-tri-O-benzyl-α-D-glucupyranosyl)uronate trichloroacetimidate in the presence of nitrile solvents and at low temperatures reproducibly gave good yields of disaccharides with high ß-selectivity. Furthermore, the use of recently reported glucuronyl thioglycoside donors protected with a cyclic 2,4-silylene acetal was found to represent another efficient and completely ß-selective way to desired disaccharide building blocks.


Assuntos
Cryptococcus neoformans/metabolismo , Cápsulas Fúngicas/efeitos dos fármacos , Cápsulas Fúngicas/metabolismo , Polissacarídeos/química , Polissacarídeos/metabolismo , Tioglicosídeos/síntese química , Tioglicosídeos/farmacologia , Configuração de Carboidratos , Técnicas de Química Sintética , Cryptococcus neoformans/efeitos dos fármacos , Glicosilação , Tioglicosídeos/química
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