Metabolic Glycoengineering with N‐Acyl Side Chain Modified Mannosamines

Abstract

In metabolic glycoengineering (MGE), cells or animals are treated with unnatural derivatives of monosaccharides. After entering the cytosol, these sugar analogues are metabolized and subsequently expressed on newly synthesized glycoconjugates. The feasibility of MGE was first discovered for sialylated glycans, by using N-acyl-modified mannosamines as precursor molecules for unnatural sialic acids. Prerequisite is the promiscuity of the enzymes of the Roseman-Warren biosynthetic pathway. These enzymes were shown to tolerate specific modifications of the N-acyl side chain of mannosamine analogues, for example, elongation by one or more methylene groups (aliphatic modifications) or by insertion of reactive groups (bioorthogonal modifications). Unnatural sialic acids are incorporated into glycoconjugates of cells and organs. MGE has intriguing biological consequences for treated cells (aliphatic MGE) and offers the opportunity to visualize the topography and dynamics of sialylated glycans in vitro, ex vivo, and in vivo (bioorthogonal MGE).

Perfluoroaryl Azide Staudinger Reaction: A Fast and Bioorthogonal Reaction

“…3), employing the widely-studied N -acetylneuraminic acid (Neu5Ac) metabolic pathway that also accommodates other monosaccharides. 5,21 PFAA-derivatized acetylated Man ( 4a ), Gal ( 4b ), and Glc ( 4c ) (Fig. 3) were synthesized by a straightforward protocol (cf.…”

“…Similar low labeling efficiency of GlcNAc derivatives was also observed by others, speculated as the restriction of GlcNAc into the sialic acid pathway, and the ability of GlcNAc analogs to produce multiple metabolic products. 21–23 …”

Catalyst‐Enabled Site‐Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors

“…Uraguchi,R.Shibazaki strates.T his situation shows that regiochemical control still heavily relies on the exploitation of the intrinsic reactivity preference of the employed substrates,especially in attaining selectivity at aremote terminal site of the conjugated acceptor. [8] TheM ichael addition of prochiral enolates to enynyl carbonyl compounds potentially produces eight isomers and their enantiomers (total of sixteen isomers,F igure 1). Herein, we report ac omplete site-divergence in the Michael addition of azlactone enolates to enynyl N-acyl pyrazoles enabled by the identification of two requisite catalysts,the cinchonidine-derived thiourea 1 and P-spiro chiral triaminoiminophosphorane 2,to afford 1,4-and 1,6-adducts,r espectively ( Figure 1), with discrete structural and stereochemical integrity.…”

“…We then thoroughly explored the scope with repsepct to the azlactones 3 in the 2i-catalyzed asymmetric 1,6-addition to 4.T he results listed in Table 2show that the incorporation of various alkyl and aryl groups onto the 4-position of 3 was tolerated and 1,6-g-Z,E-5 products were predominantly obtained with high stereoselectivities (entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. It should be noted that lowering the temperature to À40 8 8C was crucial for the additions of N-Ts-tryptophan-and phenylglycine-derived azlactones 3h and 3i,respectively,toproceed with rigorous enantiocontrol (entries 13 and 14).…”

Bioorthogonal Labeling of Human Prostate Cancer Tissue Slice Cultures for Glycoproteomics

“…[11] Motivated by these observations,w e [12] and others [13,14] have applied metabolic and bioorthogonal labeling methods to profile glycoproteins from prostate cancer cell lines using mass spectrometry (MS)-based proteomics. [17] The functionalized sialoglycoproteins are reacted with ac omplementary enrichment probe.O ne might choose among phosphine-, terminal alkyne-or cyclooctyne-functionalized probes to tag azido sialic acids,o ra na zide-functionalized probe to tag alkynyl sialic acids. These compounds are converted by the Roseman-Warren pathway into the corresponding sialic acid derivatives,which are,i nt urn, incorporated into sialoglycoproteins.…”