Efficient Strategy For Chemical Synthesis Of The Three Core Structures Of O-Mannose Glycans

O-mannose glycans is an important protein post-translational modification process in brain and muscle development,and plays a vital role in a variety of physiological and pathological processes.With the rapid development of glycoproteomics,more and more O-mannose proteins and O-mannosyl glycans have been discovered.O-mannose glycans is quite abundant in mammalian brain tissue,accounting for 30%of all O-linked glycans.To date,more than 50 mammalian O-mannose proteins have been identified,and the glycan structures of more than 20 O-mannose proteins have been fully characterized.However,the structure of such glycan chains is relatively complex and diverse,and it is difficult to extract and isolate a sufficient amount of high-purity and well-defined glycan chains from nature,which limits their biological related research.In recent years,more and more sugar researchers have used chemical methods and chemical enzymatic methods to synthesize such structurally determined glycan chains and their conjugates and conducted related research.It has been reported that O-mannosyl glycans proteoglycan affects the occurrence and development of many human diseases,such as viral infection,cancer,and metastasis of tumors;Among them,a-dystroglycan(ca-DG)is closely related to muscular dystrophy,and thus has become the most studied O-mannosylated protein in recent years.a-DG is a highly glycosylated protein found in muscle and brain tissues and plays an important role in muscle structure and function.Its unusual O-mannosylation can destroy the function of dystroglycan receptors,affecting the growth,development,repair and signaling of the nervous system,leading to various types of congenital muscular dystrophy(CMDs).O-mannosyl glycans are mainly composed of three core structures(Core M1,Core M2,Core M3)The structure of more than 20 kinds of O-mannosyl glycans was well characterized.Core M1 contains ?1-2-linked GlcNAc residue,Core M2 contains?1-2 and ?1-6-linked GlcNAc residue,and Core M3 contains ?1-4-linked GlcNAc residue.Because of its strong branching and diverse glycan structure,one of the branches is usually selected for research.So far,no relevant personnel have synthesized its overall structure.In view of the above problems,this paper takes O-mannosyl glycans,a research hotspot of chemical glycobiology,as the research object,and quickly and efficiently synthesizes its three core structures as the target.Using chemical aggregation synthesis strategy,starting from an important intermediate,the glycan chain extension was carried out by protecting group operation and chemical glycosidation respectively,and realized the gram-level synthesis of three core structural glycosyl amino acids.This method lays a foundation for the further synthesis of high-purity,structurally uniform,structurally defined glycoconjugates.The structural confirmation and structure-activity relationships and functional studies of such glycoproteins provide important prerequisites for the development of carbohydrate vaccines and carbohydrate drugs.This research mainly carried out the following aspects:(1)Flexible use of the“cyanide effect”for high regioselective protection of the 2,3-hydroxyl group of mannose;and efficient and large-scale preparation of important intermediates required for the three core branches through a reasonable protection strategy;(2)The gram-level synthesis of three core structure glycosyl amino acids of O-mannosyl glycans was achieved by different protecting group operations and glycosidation strategies based on the designed intermediates;The innovation of this article:Flexible use of the "cyaide effect" for the efficient,high-area selective acylation protection of the 2,3-hydroxyl group of mannose,and the development of a large number of synthetic strategies for the preparation of intermediates of the three core structures of O-mannosyl glycans;A gram-level chemical synthesis of three core structural glycosyl amino acids of O-mannosyl glycans was achieved.