This proposal brings together two PI's and their laboratories with distinct but overlapping expertise in the glycochemistry, both from the metropolitan Detroit area, with the aim of developing new and robust technology and methodology for the synthesis of oligosaccharides and their conjugates, such as might be readily applied by non- specialists. The proposal focuses on biologically active oligosaccharides from the microbial glycome and selects particular targets based on the biological relevance and the chemical challenges they present. The proposal aims to develop new, improved, and robust general technologies and methodology for glycosylation that will make glycosylation both more efficient and less wasteful in terms of resources. According to this paradigm flow and microwave flow methods will be developed for the preparation of glycosyl donors, acceptors and promotors, and their eventual use in scalable glycosylation reactions. These technologies will be applied to existing methodologies for glycosidic bond formation and in conjunction with the novel concepts of recyclable photochromic glycosyl donors, and of glycosyl donors that are only activated on demand in the confines of a supramolecular complex combining the donor, acceptor and activator. The proposal seeks to make all building blocks, promotors and oligosaccharides on larger scales than have heretofore been possible and to make the so-formed materials available for use in the broader community, especially by non- specialist laboratories.
Carbohydrates, glycans, and their conjugates play critical roles in a very broad spectrum of biological processes, many of which are central to human health, development and disease states. The enormous diversity of glycan-dependent biological processes is reflected by the even-more diverse spectrum and complexity of the implicated glycans and glycoconjugates, collectively known as the glycome. The study of glycan dependent biological processes and their eventual regulation and/or exploitation in human medicine is enormously hampered by difficulties in isolating and structurally characterizing meaningful quantities of pure unique glycans rather than complex mixtures of closely related substances from biological sources. Therefore, as recognized in a recent report from the National Academy of Sciences on the importance of glycomics and the glycosciences, a premium is placed on the chemical and chemoenzymatic synthesis of homogeneous glycoforms and their conjugates. Many advances have been made in the field of oligosaccharide and glycoconjugate synthesis in the last two decades such that individual glycans of great complexity can now be accessed by accomplished practitioners of the art. These syntheses, however, remain long, complex, and fraught with often unanticipated difficulties that render them unpredictable and mostly inaccessible to the non-specialist. In view of these difficulties and the sheer numbers of oligosaccharides needing to be synthesized, the oft-stated goal of the preparation of the entire glycome and its display in a format suitable for rapid and routine screening is at present somewhat unrealistic and at the very least several years away. In order to achieve this goal in the near rather than long term future, technologies for glycan synthesis need to be greatly improved. With this in mind, a team of two PIs with expertise in different areas of carbohydrate chemistry and synthetic organic methodology in general has been assembled. The team aims to develop exactly the kind of robust technology and methodology that is required to address the chemical synthesis of a broad representative cross section of the glycome and to do so in such a manner that the methods may be practiced by the non-specialist. Emphasis will be placed on robustness, scalability, ease of operation, efficiency, and the elimination of waste such that glycosylation will become more straightforward, efficient, and easy to practice for the non-specialist. All methods developed will be demonstrated through application to the synthesis of multiple complex biologically relevant microbial glycans.
| Adero, Philip Ouma; Amarasekara, Harsha; Wen, Peng et al. (2018) The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1-SN2 Interface. Chem Rev 118:8242-8284 |
