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1.
J Am Chem Soc ; 146(25): 17414-17427, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38865166

RESUMO

The high affinity interaction between P-selectin glycoprotein ligand-1 (PSGL-1) and P-selectin is mediated by a multimotif glycosulfopeptide (GSP) recognition domain consisting of clustered tyrosine sulfates and a Core 2 O-glycan terminated with sialyl LewisX (C2-O-sLeX). These distinct GSP motifs are much more common than previously appreciated within a wide variety of functionally important domains involved in protein-protein interactions. However, despite the potential of GSPs to serve as tools for fundamental studies and prospects for drug discovery, their utility has been limited by the absence of chemical schemes for synthesis on scale. Herein, we report the total synthesis of GSnP-6, an analogue of the N-terminal domain of PSGL-1, and potent inhibitor of P-selectin. An efficient, scalable, hydrogenolysis-free synthesis of C2-O-sLeX-Thr-COOH was identified by both convergent and orthogonal one-pot assembly, which afforded this crucial building block, ready for direct use in solid phase peptide synthesis (SPPS). C2-O-sLeX-Thr-COOH was synthesized in 10 steps with an overall yield of 23% from the 4-O,5-N oxazolidinone thiosialoside donor. This synthesis represents an 80-fold improvement in reaction yield as compared to prior reports, achieving the first gram scale synthesis of SPPS ready C2-O-sLeX-Thr-COOH and enabling the scalable synthesis of GSnP-6 for preclinical evaluation. Significantly, we established that GSnP-6 displays dose-dependent inhibition of venous thrombosis in vivo and inhibits vaso-occlusive events in a human sickle cell disease equivalent microvasculature-on-a-chip system. The insights gained in formulating this design strategy can be broadly applied to the synthesis of a wide variety of biologically important oligosaccharides and O-glycan bearing glycopeptides.


Assuntos
Glicopeptídeos , Glicoproteínas de Membrana , Selectina-P , Glicopeptídeos/síntese química , Glicopeptídeos/química , Glicopeptídeos/farmacologia , Selectina-P/antagonistas & inibidores , Selectina-P/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Humanos , Animais , Camundongos
2.
Chemistry ; : e202401214, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38684455

RESUMO

Reported herein is a new HPLC-based automated synthesizer (HPLC-A) capable of a temperature-controlled synthesis and purification of carbohydrates. The developed platform allows to perform various protecting group manipulations as well as the synthesis of O- and N-glycosides. A fully automated synthesis and purification was showcased in application to different carbohydrate derivatives including glycosides, oligosaccharides, glycopeptides, glycolipids, and nucleosides.

3.
Chemistry ; 29(64): e202302288, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37639512

RESUMO

Human milk oligosaccharides (HMO) have emerged as a very active area of research in glycoscience and nutrition. HMO are involved in the early development of infants and may help to prevent certain diseases. The development of chemical methods for obtaining individual HMO aids the global effort dedicated to understanding the roles of these biomolecules. Reported herein is the chemical synthesis of two common core hexasaccharides found in human milk, i. e. para-lacto-N-hexaose (pLNH) and para-lacto-N-neohexaose (pLNnH). After screening multiple leaving groups and temporary protecting group combinations, a 3+3 convergent coupling strategy was found to work best for obtaining these linear glycans.


Assuntos
Leite Humano , Oligossacarídeos , Lactente , Humanos , Leite Humano/química , Oligossacarídeos/química , Polissacarídeos/análise , Hidrolases
4.
Chemistry ; 29(43): e202300873, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37154481

RESUMO

Reported herein is the development of a novel method for activating thioglycosides without a glycosyl halide intermediate. This has been achieved through the use of a silver salt coupled with an acid additive and molecular iodine. The enhanced stereocontrol was achieved via the H-bond mediated aglycone delivery (HAD) method, and the extended trisaccharide synthesis was achieved via iteration of deprotection and glycosylation steps.

5.
Molecules ; 27(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36364179

RESUMO

Reported herein is a new protocol for glycosidation of alkyl and aryl thioglycosides in the presence of copper(II) bromide. While the activation with CuBr2 alone was proven suitable for reactive glycosyl donors, the activation of less reactive donors was more efficient in the presence of triflic acid as an additive. A variety of thioglycoside donors in reactions with different glycosyl acceptors were investigated to determine the initial scope of this reaction.


Assuntos
Tioglicosídeos , Glicosilação , Brometos , Cobre
6.
Chemistry ; 28(39): e202201180, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35513346

RESUMO

As the 21st century unfolds with rapid changes, new challenges in research and development emerge. These new challenges prompted us to repurpose our HPLC-A platform that was previously used in solid phase glycan synthesis to a solution phase batch synthesis described herein. The modular character of HPLC allows for implementing new attachments. To enable sequential synthesis of multiple oligosaccharides with the single press of a button, we supplemented our system with a four-way split valve and an automated fraction collector. This enabled the operator to load all reagents and all reactants in the autosampler, press the button to start the repetitive automation sequence, leave the lab, and upon return find products of multiple reactions ready for purification, analysis, and subsequent application.


Assuntos
Oligossacarídeos , Polissacarídeos , Automação , Cromatografia Líquida de Alta Pressão , Técnicas de Síntese em Fase Sólida
7.
Chemistry ; 28(14): e202103747, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-34935219

RESUMO

Thioglycosides are among the most common glycosyl donors that find broad application in the synthesis of glycans and glycoconjugates. However, the requirement for toxic and/or large access of activators needed for common glycosylations with thioglycosides remains a notable drawback. Due to the increased awareness of the chemical waste impact on the environment, synthetic studies have been driven by the goal of finding non-toxic reagents. The main focus of this review is to highlight recent methods for thioglycoside activation that rely on transition metal catalysis.


Assuntos
Tioglicosídeos , Elementos de Transição , Catálise , Glicoconjugados , Glicosilação
8.
Org Biomol Chem ; 19(9): 2044-2054, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33599667

RESUMO

Described herein is the first example of glycosidation of thioglycosides in the presence of palladium(ii) bromide. While the activation with PdBr2 alone was proven feasible, higher yields and cleaner reactions were achieved when these glycosylations were performed in the presence of propargyl bromide as an additive. Preliminary mechanistic studies suggest that propargyl bromide assists the reaction by creating an ionizing complex, which accelerates the leaving group departure. A variety of thioglycoside donors in reactions with different glycosyl acceptors were investigated to determine the initial scope of this new reaction. Selective and chemoselective activation of thioglycosides over other leaving groups has also been explored.


Assuntos
Paládio/química , Tioglicosídeos/química , Catálise , Dissacarídeos/síntese química , Glicosilação , Pargilina/análogos & derivados , Pargilina/química
9.
Chemistry ; 27(1): 354-361, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32804435

RESUMO

Our group has previously reported that 3,3-difluoroxindole (HOFox) is able to mediate glycosylations via intermediacy of OFox imidates. Thioglycoside precursors were first converted into the corresponding glycosyl bromides that were then converted into the OFox imidates in the presence of Ag2 O followed by the activation with catalytic Lewis acid in a regenerative fashion. Reported herein is a direct conversion of thioglycosides via the regenerative approach that bypasses the intermediacy of bromides and eliminates the need for heavy-metal-based promoters. The direct regenerative activation of thioglycosides is achieved under neutral reaction conditions using only 1 equiv. NIS and catalytic HOFox without the acidic additives.


Assuntos
Brometos , Tioglicosídeos , Brometos/química , Catálise , Glicosilação , Ácidos de Lewis , Tioglicosídeos/química
10.
J Org Chem ; 84(23): 15052-15062, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31718181

RESUMO

A novel 8-O-picoloylated sialyl donor has been developed, and the performance of various picoloylated sialyl donors in glycosylations with primary glycosyl acceptors has been evaluated. 8-O-Picoloyl and 4,9-di-O-picoloyl sialyl donors produced moderate to excellent yields of disaccharides with complete α-stereoselectivities. Synergistic effects between picoloyl and the accompanying O-protecting groups (benzoyl vs acetyl) were evaluated, as well as the effects of triflic acid concentration on the 8-O-picoloyl donor. 1H NMR analysis was also carried out to assess differences in the hydrogen-bonding net between sialyl donors.


Assuntos
Dissacarídeos/síntese química , Ácidos Siálicos/química , Configuração de Carboidratos , Dissacarídeos/química , Glicosilação , Ligação de Hidrogênio , Estereoisomerismo
11.
Org Biomol Chem ; 17(36): 8379-8383, 2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31490529

RESUMO

An efficient synthesis of thioglycosides from per-acetates in the presence of triflic acid is described. The developed protocol features high reaction rates and product yields. Some reactive sugar series give high efficiency in the presence of sub-stoichiometric trifluoromethanesulfonic acid (TfOH) in contrast to other known protocols that require multiple equivalents of Lewis acids to reach high conversion rates.


Assuntos
Mesilatos/química , Tioglicosídeos/síntese química , Configuração de Carboidratos , Tioglicosídeos/química
12.
Org Lett ; 19(10): 2638-2641, 2017 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-28453277

RESUMO

The stereoselective synthesis of sialosides is still one of the major challenges in carbohydrate chemistry. The synthesis and glycosidation of novel sialyl donors bearing a picoloyl substituent at C-4 are reported. High stereoselectivities and faster reactions were observed in the presence of an excess of triflic acid. The acid excess does not have the same effect on conventional sialyl donors, which suggests a possible synergistic effect of the picoloyl substituent and the triflic acid.

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