Synthesis of uridine 5′-(2-acetamido-2,4-dideoxy-4-fluoro-α-d-galactopyranosyl) diphosphate and uridine 5′-(2-acetamido-2,6-dideoxy-6-fluoro-α-d-glucopyranosyl) di-phosphate

Thomas, Rexford L.; Abbas, Saeed A.; Matta, Khushi L.

doi:10.1016/0008-6215(88)80007-7

Cited by 10 publications

(2 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, unnatural monosaccharides are incorporated into cellular glycoconjugates. [20][21][22][23][24] Although analogs of galactose, GlcNAc, GalNAc, and mannose have been synthesized, only limited studies have been conducted in cellular assays. [25][26][27] 4F-GlcNAc is an example of this class of inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins

Marathe

Buffone

Chandrasekaran³

et al. 2010

Blood

Self Cite

View full text Add to dashboard Cite

Novel strategies to control the binding of adhesion molecules belonging to the selectin family are required for the treatment of inflammatory diseases. We tested the possibility that synthetic monosaccharide analogs can compete with naturally occurring sugars to alter the O-glycan content on human leukocyte cell surface selectin-ligand, P-selectin glycoprotein ligand-1 (PSGL-1). Resulting reduction in the sialyl Lewis-X-bearing epitopes on this ligand may reduce cell adhesion. Consistent with this hypothesis, 50Mper-acetylated 4F-GalNAc added to the growth media of promyelocytic HL-60 cells reduced the expression of the cutaneous lymphocyte associated-antigen (HECA-452 epitope) by 82% within 2 cell doubling cycles. Cell binding to all 3 selectins (L-, E-, and P-selectin) was reduced in vitro. 4F-GalNAc was metabolically incorporated into PSGL-1, and this was accompanied by an approximately 20% reduction in PSGL-1 glycan content. A 70% to 85% reduction in HECA-452 binding epitope and N-acetyl lactosamine content in PSGL-1 was also noted on 4F-GalNAc addition. Intravenous 4F-GalNAc infusion reduced leukocyte migration to the peritoneum in a murine model of thioglycolate-induced peritonitis. Thus, the compound has pharmacologic activity. Overall, the data suggest that 4F-GalNAc may be applied as a metabolic inhibitor to reduce O-linked glycosylation, sialyl Lewis-X formation, and leukocyte adhesion via the selectins. (Blood. 2010;115:1303-1312) IntroductionThe binding of adhesion molecules belonging to the selectin family to carbohydrate ligands facilitates the adhesion of blood leukocytes to activated endothelial cells, platelets, and other leukocytes in the human vasculature. 1,2 Such molecular interactions play an important role in regulating leukocyte recruitment at sites of inflammation, cancer metastasis, and various cardiovascular disorders. 3 Whereas numerous glycoproteins and glycolipids participate in selectin-mediated cell adhesion, interactions with carbohydrate epitopes expressed on the leukocyte glycoprotein P-selectin glycoprotein ligand-1 (PSGL-1, CD162) are particularly important because this ligand binds all 3 members of the selectin family (E-, P-, and L-selectin) with high affinity and under fluid flow conditions. Structural analysis of the glycans of PSGL-1 expressed on human promyelocytic leukemia HL-60 cells reveals that PSGL-1 is predominantly composed of core-2 based O-linked glycans. 4,5 The prototypic selectin-binding carbohydrate structure sialyl Lewis-X (NeuAc␣2,3Gal␤1,4(Fuc␣1,3)GlcNAc-, sLe X ; Figure 1A) is expressed on 2% to 14% of these O-glycans.There is active interest in developing antagonists that control/ block selectin-mediated cell adhesion using either competitive inhibitors or metabolic inhibitors. Competitive inhibitors attempt to block cell adhesion by regulating the ligand-binding epitope of either the selectin or its primary counter-receptor PSGL-1. Antagonists used for such inhibition include the tetrasaccharide sLe X and its glycomimetics, 6 humanized antibodies direc...

show abstract

Section: Introductionmentioning

confidence: 99%

Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins

Marathe

Buffone

Chandrasekaran³

et al. 2010

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pure α anomer 16a was 3′-benzoylated to yield 17, and the 4′-position was unlocked by the reductive opening of the 4′,6′-benzylidene ring, allowing smooth conversion of compound 18 with DAST in DCM to 4′-fluorinated galactosamine analogue 19 in 84% yield. This is one of the high-yielding 4′-axial fluorinations of a 2-azido sugar reported to date. − Removal of the 3′-benzoate ester afforded acceptor 20 .…”

Section: Resultsmentioning

confidence: 95%

Glycoamino Acid Analogues of the Thomsen–Friedenreich Tumor-Associated Carbohydrate Antigen: Synthesis and Evaluation of Novel Antiproliferative Factor Glycopeptides

et al. 2017

View full text Add to dashboard Cite

Glycoamino acid analogues of the Thomsen–Friedenreich antigen disaccharide, where the 4′ and 4″ hydroxyl groups were substituted with fluorine or hydrogen, were synthesized and incorporated into the asialylated antiproliferative factor (as-APF), a biologically active form of APF, a glycopeptide found in the urine of patients with interstitial cystitis. Various strategies were employed to incorporate the fluorine atom at the 4-positions of either the galactose or N-acetylgalactosamine unit of the disaccharide antigen, based on stereochemistry and reactivity. These glycopeptides were evaluated in antiproliferative assays on both primary normal bladder epithelial cells and T24 bladder carcinoma cells. Unlike many previously published substitutions to APF, mono-4′-fluorination of the GalNAc residue did not affect the activity, whereas fluoro-derivatives of the galactose 4″-position or both 4′ and 4″ hydroxyls showed a reduced potency relative to the monosubstituted GalNAc derivative. A fourth compound where the 4″ position of galactose was deoxygenated showed a lower potency than the parent and monosubstituted compounds. These results suggest that specific substitutions in the sugar moieties in the APF can be tolerated, and the glycomimetic design of APF analogues can include fluorine in the GalNAc sugar of the disaccharide.

show abstract

Synthesis of Sugar Nucleotides

Öhrlein

Ernst

Hart

et al. 2000

Carbohydrates in Chemistry and Biology

View full text Add to dashboard Cite

Recent progress in molecular glycobiology has revealed the important biological roles of numerous glycoconjugates [ 11. In particular cell-surface carbohydrates play key roles in cellular communication processes via selective adhesion phenomena [2, 31. They guide e.g. leukocyte extravasation [4], the homing of lymphocytes and adhesion of myeloid cells to activated platelets and the endothelium [5][6][7]. Besides these interactions carbohydrates are involved in fertilization events, cell growth, and parasitic infections of viruses and bacteria 181. A very recent finding is the involvement of certain cell surface a-galactosides in hyperacute rejection reactions; this is of pharmaceutical interest in organ transplantation 191.This makes sugars worthwhile targets for pharmaceutical applications [ 10, 1 11. Although chemical synthesis of oligosaccharides has reached a mature stage [ 12-141 the overall synthetic sequences are still lengthy and cumbersome [ 151. Biologically active carbohydrates are, moreover, composed of various different monosaccharide units and are often only active if presented in a polyvalent or multiantennary array to their respective receptors [ 16, 171. These multiantennary heteropolymers, in particular, have resisted efficient chemical synthesis. Recently biocatalysts have been found to be valuable tools for complementing the classical synthetic approach [ 181.Nature has invented several ways of assembling complex oligosaccharides [ 11. The Leloir pathway is one of the preferred routes of mammalian systems. The Leloir enzymes-the glycosyl transferases-transfer a monosaccharide unit from a nucleotide-activated donor substrate to a growing oligosaccharide chain with rigorous regio-and stereoselectivity [19] (see Scheme 1). Exclusively one of the many OH groups of the acceptor is glycosylated, in either an a or p mode! Neither the donor nor the acceptor sugar needs protection from the highly homofunctional reactants-often OH groups only are present on the sugars. Thus, selective protecting group manipulations, a preponderant task in the classical, chemical oligosaccharide assemblage can be reduced to an absolute minimum.

show abstract

Synthesis of uridine 5′-(2-acetamido-2,4-dideoxy-4-fluoro-α-d-galactopyranosyl) diphosphate and uridine 5′-(2-acetamido-2,6-dideoxy-6-fluoro-α-d-glucopyranosyl) di-phosphate

Cited by 10 publications

References 16 publications

Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins

Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins

Glycoamino Acid Analogues of the Thomsen–Friedenreich Tumor-Associated Carbohydrate Antigen: Synthesis and Evaluation of Novel Antiproliferative Factor Glycopeptides

Synthesis of Sugar Nucleotides

Contact Info

Product

Resources

About