The glycocalyx, a thick layer of carbohydrates, surrounds the cell wall of most bacterial and parasitic pathogens. Recognition of these unique glycans by the human immune system results in ...destruction of the invaders. To elicit a protective immune response, polysaccharides either isolated from the bacterial cell surface or conjugated with a carrier protein, for T-cell help, are administered. Conjugate vaccines based on isolated carbohydrates currently protect millions of people against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitides infections. Active pharmaceutical ingredients (APIs) are increasingly discovered by medicinal chemistry and synthetic in origin, rather than isolated from natural sources. Converting vaccines from biologicals to pharmaceuticals requires a fundamental understanding of how the human immune system recognizes carbohydrates and could now be realized. To illustrate the chemistry-based approach to vaccine discovery, I summarize efforts focusing on synthetic glycan-based medicinal chemistry to understand the mammalian antiglycan immune response and define glycan epitopes for novel synthetic glycoconjugate vaccines against Streptococcus pneumoniae, Clostridium difficile, Klebsiella pneumoniae, and other bacteria. The chemical tools described here help us gain fundamental insights into how the human system recognizes carbohydrates and drive the discovery of carbohydrate vaccines.
Carbohydrates are the most abundant biopolymers on earth and part of every living creature. Glycans are essential as materials for nutrition and for information transfer in biological processes. To ...date, in few cases a detailed correlation between glycan structure and glycan function has been established. A molecular understanding of glycan function will require pure glycans for biological, immunological, and structural studies. Given the immense structural complexity of glycans found in living organisms and the lack of amplification methods or expression systems, chemical synthesis is the only means to access usable quantities of pure glycan molecules. While the solid-phase synthesis of DNA and peptides has become routine for decades, access to glycans has been technically difficult, time-consuming and confined to a few expert laboratories. In this Account, the development of a comprehensive approach to the automated synthesis of all classes of mammalian glycans, including glycosaminoglycans and glycosylphosphatidyl inositol (GPI) anchors, as well as bacterial and plant carbohydrates is described. A conceptual advance concerning the logic of glycan assembly was required in order to enable automated execution of the synthetic process. Based on the central glycosidic bond forming reaction, a general concept for the protecting groups and leaving groups has been developed. Building blocks that can be procured on large scale, are stable for prolonged periods of time, but upon activation result in high yields and selectivities were identified. A coupling–capping and deprotection cycle was invented that can be executed by an automated synthesis instrument. Straightforward postsynthetic protocols for cleavage from the solid support as well as purification of conjugation-ready oligosaccharides have been established. Introduction of methods to install selectively a wide variety of glycosidic linkages has enabled the rapid assembly of linear and branched oligo- and polysaccharides as large as 30-mers. Fast, reliable access to defined glycans that are ready for conjugation has given rise to glycan arrays, glycan probes, and synthetic glycoconjugate vaccines. While an ever increasing variety of glycans are accessible by automated synthesis, further methodological advances in carbohydrate chemistry are needed to make all possible glycans found in nature. These tools begin to fundamentally impact the medical but also materials aspects of the glycosciences.
The glycocalyx, a thick layer of carbohydrates, surrounds the cell wall of most bacterial and parasitic pathogens. Recognition of these unique glycans by the human immune system results in ...destruction of the invaders. To elicit a protective immune response, polysaccharides either isolated from the bacterial cell surface or conjugated with a carrier protein, for T-cell help, are administered. Conjugate vaccines based on isolated carbohydrates currently protect millions of people against
,
type b, and
infections. Active pharmaceutical ingredients (APIs) are increasingly discovered by medicinal chemistry and synthetic in origin, rather than isolated from natural sources. Converting vaccines from biologicals to pharmaceuticals requires a fundamental understanding of how the human immune system recognizes carbohydrates and could now be realized. To illustrate the chemistry-based approach to vaccine discovery, I summarize efforts focusing on synthetic glycan-based medicinal chemistry to understand the mammalian antiglycan immune response and define glycan epitopes for novel synthetic glycoconjugate vaccines against
,
,
, and other bacteria. The chemical tools described here help us gain fundamental insights into how the human system recognizes carbohydrates and drive the discovery of carbohydrate vaccines.
The synthesis of complex molecules requires control over both chemical reactivity and reaction conditions. While reactivity drives the majority of chemical discovery, advances in reaction condition ...control have accelerated method development/discovery. Recent tools include automated synthesizers and flow reactors. In this Synopsis, we describe how flow reactors have enabled chemical advances in our groups in the areas of single-stage reactions, materials synthesis, and multistep reactions. In each section, we detail the lessons learned and propose future directions.
Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small ...molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative
or linear processes
, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide
, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon-nitrogen cross-couplings
in a photochemical module-all without instrument reconfiguration.
Polysaccharides are the most abundant biopolymers on earth that serve various structural and modulatory functions. Pure, completely defined linear and branched polysaccharides are essential to ...understand carbohydrate structure and function. Polysaccharide isolation provides heterogeneous mixtures, while heroic efforts were required to complete chemical and/or enzymatic syntheses of polysaccharides as long 92-mers. Here, we show that automated glycan assembly (AGA) enables access to a 100-mer polysaccharide via a 201-step synthesis within 188 h. Convergent block coupling of 30- and 31-mer oligosaccharide fragments, prepared by AGA, yielded a multiple-branched 151-mer polymannoside. Quick access to polysaccharides provides the basis for future material science applications of carbohydrates.
Polysaccharides are Nature’s most abundant biomaterials essential for plant cell wall construction and energy storage. Seemingly minor structural differences result in entirely different functions: ...cellulose, a β (1–4) linked glucose polymer, forms fibrils that can support large trees, while amylose, an α (1–4) linked glucose polymer forms soft hollow fibers used for energy storage. A detailed understanding of polysaccharide structures requires pure materials that cannot be isolated from natural sources. Automated Glycan Assembly provides quick access to trans-linked glycans analogues of cellulose, but the stereoselective installation of multiple cis-glycosidic linkages present in amylose has not been possible to date. Here, we identify thioglycoside building blocks with different protecting group patterns that, in concert with temperature and solvent control, achieve excellent stereoselectivity during the synthesis of linear and branched α-glucan polymers with up to 20 cis-glycosidic linkages. The molecules prepared with the new method will serve as probes to understand the biosynthesis and the structure of α-glucans.
Malaria is a serious global health issue. Artemisinin combination treatments are the first‐line drugs, but supplies are limited because artemisinin is obtained solely by extraction from Artemisia ...annua. A continuous‐flow process that converts dihydroartemisinic acid into artemisinin (see scheme) was shown to be an inexpensive and scalable process that can ensure a steady, affordable supply of artemisinin.
The Hitchhiker’s Guide to Flow Chemistry Plutschack, Matthew B; Pieber, Bartholomäus; Gilmore, Kerry ...
Chemical reviews,
09/2017, Letnik:
117, Številka:
18
Journal Article
Recenzirano
Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction ...parameters enhancing reactivity or in some cases enabling new reactions. This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, “Should we do this in flow?” has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts.
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