Synthesis of hyaluronic-acid-related oligosaccharides and analogues, as their 4-methoxyphenyl glycosides, having N-acetyl-β-d-glucosamine at the reducing end

Halkes, Koen M.; Slaghek, Ted M.; Hyppönen, Teija K.; Kruiskamp, P.H.; Ogawa, Tomoya; Kamerling, Johannis P.; Vliegenthart, Johannes F.G.

doi:10.1016/s0008-6215(98)00116-5

Cited by 20 publications

(15 citation statements)

References 28 publications

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“…In contrast, the enzyme is the "perfect" carbohydrate chemist, performing sugar additions with no side-products in aqueous solution. The largest HA oligosaccharide synthesized by chemical means to date was the hexasaccharide (HA6), containing a methoxyphenyl group at the reducing terminus (18). Although it is a very nice example, this product is too small for the interesting biological activities described ear-FIG.…”

Section: Discussionmentioning

confidence: 99%

Rapid Chemoenzymatic Synthesis of Monodisperse Hyaluronan Oligosaccharides with Immobilized Enzyme Reactors

DeAngelis

Oatman

Gay

2003

Journal of Biological Chemistry

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We describe the chemoenzymatic synthesis of a variety of monodisperse hyaluronan (␤4-glucuronic acid-␤3-N-acetylglucosamine (HA)) oligosaccharides. Potential medical applications for HA oligosaccharides (ϳ10 -20 sugars in length) include killing cancerous tumors and enhancing wound vascularization. Previously, the lack of defined oligosaccharides has limited the exploration of these sugars as components of new therapeutics. The Pasteurella multocida HA synthase, pmHAS, a polymerizing enzyme that normally elongates HA chains rapidly (ϳ1-100 sugars/s), was converted by mutagenesis into two single-action glycosyltransferases (glucuronic acid transferase and N-acetylglucosamine transferase). The two resulting enzymes were purified and immobilized individually onto solid supports. The two types of enzyme reactors were used in an alternating fashion to produce extremely pure sugar polymers of a single length (up to HA20) in a controlled, stepwise fashion without purification of the intermediates. These molecules are the longest, non-block, monodisperse synthetic oligosaccharides hitherto reported. This technology platform is also amenable to the synthesis of medicanttagged or radioactive oligosaccharides for biomedical testing. Furthermore, these experiments with immobilized mutant enzymes prove both that pmHAS-catalyzed polymerization is non-processive and that a monomer of enzyme is the functional catalytic unit.Complex carbohydrates play many essential roles in vertebrates, but these molecules are often difficult to isolate or to synthesize in pure form and in large amounts for study. HA, 1 a member of the glycosaminoglycan polysaccharide family that includes heparin and chondroitin, is a repeating ␤4-glucuronic acid-␤3-N-acetylglucosamine polymer that is prevalent in the vertebrate body. HA has numerous essential roles in mammals, including modulation of cellular adhesion, signaling, and motility (1, 2). The polymer is thought to be synthesized initially as a chain of ϳ10 5-6 Da (ϳ10 3-4 sugars), which then degrades during turnover in the body to generate a variety of smaller polymers. Although the mechanisms are not completely understood, it has been observed that the size of the HA polymer dictates its effect on cells. Various cell-surface receptors or binding proteins, termed hyaladherins, are postulated to sense the presence and the size of HA (3-5). Hyaladherins thought to play important roles include CD44 and RHAMM. Multivalent binding and/or multimerization of receptors may potentially occur with large polymers but not with small chains, resulting in the alteration of various signaling events.Recently, several groups have reported that HA oligosaccharides (ϳ2-3.5 kDa or ϳ10 -17 sugars) have extremely interesting effects on cellular behavior. These small sugar molecules induce a variety of cancer cells to undergo programmed cell death or apoptosis (6, 7). This intriguing finding immediately suggests the use of HA oligosaccharides as an aid to chemotherapy or radiation treatments to reduce tumor load or limit...

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Section: Discussionmentioning

confidence: 99%

Rapid Chemoenzymatic Synthesis of Monodisperse Hyaluronan Oligosaccharides with Immobilized Enzyme Reactors

DeAngelis

Oatman

Gay

2003

Journal of Biological Chemistry

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“…Pyranosyl uronic acids such as glucoronic acid, galactonic acid, and mannosinic acid often exist in oligosaccharides and selectively protected uronic acids are useful for carbohydrate synthesis. [11,18] Conversion of the free primary hydroxyl groups in galactoside 9, glucoside 11, [21] 2-deoxy-2-amino-glucoside derivatives 13 and 16, and mannoside 18 [22] to the corresponding uronic acids proceeded smoothly in 82-92% yields (Table 1, entries 4-8). Acid-sensitive isopropylidene and p-methoxybenzyl (PMB) groups were stable under reaction conditions (Table 1, entries 4 and 6).…”

Section: Resultsmentioning

confidence: 99%

“…With this strategy, one of the key challenges is the need to convert primary hydroxyl groups at C-6 positions into carboxylic acids post glyco-assembly. The traditional pyridinium dichromate (PDC) mediated oxidation, [9][10][11] was found to be inefficient; it often required large excess of PDC subsequently resulting in separation difficulties and low yields. [6,9] Two-step protocols, such as Swern oxidation followed by treatment of NaClO 2 or PDC, [7,12] not only are inconvenient, but also can produce elimination side products due to the strongly basic condition utilized.…”

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confidence: 99%

A Facile Method for Oxidation of Primary Alcohols to Carboxylic Acids and Its Application in Glycosaminoglycan Syntheses

Huang

Teumelsan

Huang

2006

Chemistry A European J

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A convenient two-step, one-pot procedure was developed for the conversion of primary alcohols to carboxylic acids. The alcohol was first treated with NaOCl and TEMPO under phase-transfer conditions, followed by NaClO 2 oxidation in one pot. This reaction is applicable to a wide range of alcohols and the mild reaction conditions are compatible with many sensitive functional groups, including electron-rich aromatic rings, acid-labile isopropylidene ketal and glycosidic linkages, and oxidation-prone thioacetal, p-methoxybenzyl, and allyl moieties. Several glycosaminoglycans such as heparin, chondroitin, and hyaluronic acid oligosaccharides have been synthesized in high yields by using this new oxidation protocol.

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“…[20] Due to the low reactivity of glucuronic acid, as an alternative, more reactive glucose can be used as building blocks. [21][22][23][24][25][26][27] With this strategy, a selectively removable protective group must be installed on the 6-hydroxyl group of glucose to allow for oxidation-state adjustment. The complete deprotection and oxidation of 6-OH on all glucose units can present significant challenges.…”

Section: Introductionmentioning

confidence: 99%

“…[5,[19][20][21][22][23][24][25][26][27] To facilitate biological studies of sHA, a robust method needs to be developed so that fast and efficient assembly of multiple sHA can be achieved.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Syntheses of Hyaluronic Acid Oligosaccharides

Huang

2006

Chemistry A European J

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Highly efficient syntheses of hyaluronic acid oligosaccharides have been accomplished through the pre-activation based iterative one-pot strategy. A series of oligosaccharides ranging from di-to hexasaccharides were rapidly assembled using only near stoichiometric amounts of the building blocks without aglycon adjustment or purifications of intermediate oligosaccharides. Deprotection and oxidation protocols were developed for protective group removal and oxidation-state adjustment. The availability of such structurally well defined synthetic hyaluronic acid oligosaccharides will greatly facilitate the establishment of detailed structure-function relationships.

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Synthesis of hyaluronic-acid-related oligosaccharides and analogues, as their 4-methoxyphenyl glycosides, having N-acetyl-β-d-glucosamine at the reducing end

Cited by 20 publications

References 28 publications

Rapid Chemoenzymatic Synthesis of Monodisperse Hyaluronan Oligosaccharides with Immobilized Enzyme Reactors

Rapid Chemoenzymatic Synthesis of Monodisperse Hyaluronan Oligosaccharides with Immobilized Enzyme Reactors

A Facile Method for Oxidation of Primary Alcohols to Carboxylic Acids and Its Application in Glycosaminoglycan Syntheses

Highly Efficient Syntheses of Hyaluronic Acid Oligosaccharides

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