Phase-Transfer-Catalysed Synthesis of N-Acetylneuraminic Acid α-Thioketosides and Inhibitor Studies with<i>Clostridium perfringens</i>Sialidase

Rothermel, Jörg; Faillard, Hans

doi:10.1515/bchm3.1989.370.2.1077

Cited by 19 publications

(7 citation statements)

References 23 publications

(16 reference statements)

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“…To prepare the target Neu5Ac derivative, the amine-functionalized Neu5Ac 2 was first synthesized in five steps starting form commercially available Neu5Ac according to previously published procedures. 29,50 Next, upon reacting 2 with thiophosgene, the isothiocyanate group was successfully installed to obtain the target molecule 3 in quantitative yield (Scheme 1). Dendron 1 was then reacted with Neu5Ac derivative 3 in the presence of NEt 3 to obtain the target Neu5Ac-functionalized dendron 4 in good yield.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In this assay, the polymersomes were compared to dendron 4 and to a monovalent Neu5Ac derivative phenyl 2-thio-α-sialoside (9). 50 LFA has been shown to be a specific lectin for Neu5Ac and Nglycolylneuraminic acid with a much greater binding affinity toward Neu5Ac. This has made it a good candidate to study Neu5Ac−protein binding.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…An isothiocyanate derivative of Neu5Ac was selected because an unprotected Neu5Ac isothiocyanate can be prepared and selectively reacted with the dendritic amines to provide a stable thiourea linkage, without the need for deprotection of the carbohydrate once on the polyester dendron backbone. To prepare the target Neu5Ac derivative, the amine-functionalized Neu5Ac 2 was first synthesized in five steps starting form commercially available Neu5Ac according to previously published procedures. , Next, upon reacting 2 with thiophosgene, the isothiocyanate group was successfully installed to obtain the target molecule 3 in quantitative yield (Scheme ). Dendron 1 was then reacted with Neu5Ac derivative 3 in the presence of NEt 3 to obtain the target Neu5Ac-functionalized dendron 4 in good yield.…”

Section: Resultsmentioning

confidence: 99%

“…With the dendritic sialopolymersomes in hand, their protein binding properties were then evaluated using an ELLA. In this assay, the polymersomes were compared to dendron 4 and to a monovalent Neu5Ac derivative phenyl 2-thio-α-sialoside ( 9 ) . LFA has been shown to be a specific lectin for Neu5Ac and N -glycolylneuraminic acid with a much greater binding affinity toward Neu5Ac.…”

Section: Resultsmentioning

confidence: 99%

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Multifunctional Dendritic Sialopolymersomes as Potential Antiviral Agents: Their Lectin Binding and Drug Release Properties

2013

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Polymer vesicles, commonly referred to as polymersomes, are self-organized materials that result from the self-assembly of amphiphilic copolymers in solution. Recently, there has been increasing interest in biomedical applications of polymersomes due to the different functions that can be imparted through encapsulation of molecules within the core or membrane or through the introduction of bioactive molecules to the polymersome surface. We describe here the development and study of poly(ethylene oxide)-polycaprolactone polymersomes designed to interact with influenza viruses at two different stages in the infection process. First, the conjugation of the sialic acid N-acetylneuraminic acid (Neu5Ac) to the polymersome surface was designed to inhibit the binding of viral hemagglutinin to sialic acids on host cells, thus preventing viral entry. Second, the incorporation of the neuraminidase inhibitor zanamivir into the polymersome core was designed to prevent the release of progeny virus from the host cells, thus inhibiting viral replication. With the aim of maximizing multivalent effects at the polymersome surface, polyester dendrons functionalized with Neu5Ac were synthesized and conjugated to polymersomes. Binding of the resulting dendritic sialopolymersomes to Limax flavus agglutinin was studied and compared to the sialodendron and a monovalent Neu5Ac derivative using an enzyme-linked lectin inhibition assay. It was found that while the sialodendron exhibited a 17-fold enhancement (per sialoside) relative to the small molecule, the dendritic sialopolymersomes resulted in an almost 2000-fold enhancement in binding affinity. It was also demonstrated that encapsulation of zanamivir into the dendritic sialopolymersomes could be performed with the same efficiency as for naked polymersomes to provide a drug loading of ~35 wt %. Drug release rates were similar for both systems with sustained release over a period of 4 days. Overall, these results suggest the promise of using a multifunctional polymersome system for interaction with and inhibition of influenza viruses.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Multifunctional Dendritic Sialopolymersomes as Potential Antiviral Agents: Their Lectin Binding and Drug Release Properties

2013

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“…The glycosidation with the benzyl ester-protected derivative was more efficient than with the methyl ester-protected derivative. The elimination reaction to the 2,3-dehydro-neuraminic acid derivative [15] was much more suppressed. 4 resulted in a yield of up to 72% whereas the analogous methyl ester component, as we reported earlier 1151 , could be obtained only in yields of up to 60%.…”

Section: Resultsmentioning

confidence: 96%

2-α-(N-Dansyl-4-aminophenylthio)-N-acetyl-9-O-acetylneuraminic Acid. A New Specific and Highly Sensitive Substrate in Sialate-O-Acetylesterase Assay

Reinhard

Becker²,

Rothermel³

et al. 1992

Biological Chemistry Hoppe-Seyler

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2-a-(N-Dansyl-4-aminophenylthio)-./Vacetyl-9-O-acetylneuraminic acid (10) was prepared as a new specific and highly sensitively detectable sialate-9-O-acetyl-esterase substrate. It is built up from a sialidase-stable aminophenyl-a-thioketoside of Nacetylneuraminic acid. By labeling this thioketoside with dansyl chloride a fluorescent neuraminic acid derivative was prepared which allows determinations down to the picomol range. Regioselective acetylation with trimethylorthoacetate results in the corresponding 9-0-acetyl derivative. After incubation with esterase from bovine brain the hydrolysis products were separated on a HPLC column and fluorimetrically detected at 334 nm excitation and 564 nm emission.The K m value of 2.5mM was in the range between the values of the completely unspecific methylumbelliferyl acetate and the less sensitively detectable A r -acetyl-9-O-acetylneuraminic acid which have been used up to now as standard substrates.Zusammenfassung: 2-a-(7V-Dansyl-4-aminophenylthio)-./V-acetyl-9-O-acetylneuraminsäure (10) wurde als neues spezifisches Sialinsäure-9-O-acetylesteraseSubstrat synthetisiert, das noch bis in den PicomolBereich nachgewiesen werden kann. Als Ausgangsverbindung diente das a-Aminophenyl-thioglycosid des Peracetylneuraminsäure-benzylesters. Die Reaktion des Thioglycosids mit Dansylchlorid ergibt ein fluoreszierendes Neuraminsäureglycosid, das durch regioselektive Acetylierung mitTrimethylorthoacetat zum entsprechenden 9-O-acetylierten Neuraminsäure-Derivat umgesetzt wird. Nach Inkubation mit Esterase aus Rinderhirn konnten die Hydrolyseprodukte mittels HPLC getrennt und fluorimetrisch bei einer Anregungswellenlänge von 334 nm und einer Emissionswellenlänge von 564 nm delektiert werden. Der Ä: m -Wert beträgt 2.5mM und liegt zwischen dem des Methylumbelliferylacetats und dem der N-Acetyl-9-O-acetylneuraminsäure, die bislang als Standardsubstrate verwendet wurden.

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Zemplén Deacetylation

2010

Comprehensive Organic Name Reactions and Reagents

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The efficient removal of the O ‐acetyl protecting groups of carbohydrates by treatment of the O ‐acetylated substrates in methanol with a catalytic amount of sodium methoxide at room temperature is generally known as the Zemplén deacetylation, Zemplén de‐ O ‐acetylation, or Zemplen deacetylation. In addition, after the reaction, the O ‐acetyl‐protected carbohydrates are transformed into unprotected ones, in a manner analogous to the hydrolysis of an ester, thus this reaction is termed as the Zemplen saponification as well. However, it has been reported that the Zemplén deacetylation is probably not suitable for the deprotection of carbohydrates with disulfide linkages. This reaction has wide applications in carbohydrate chemistry.

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Phase-Transfer-Catalysed Synthesis of N-Acetylneuraminic Acid α-Thioketosides and Inhibitor Studies withClostridium perfringensSialidase

Cited by 19 publications

References 23 publications

Multifunctional Dendritic Sialopolymersomes as Potential Antiviral Agents: Their Lectin Binding and Drug Release Properties

Multifunctional Dendritic Sialopolymersomes as Potential Antiviral Agents: Their Lectin Binding and Drug Release Properties

2-α-(N-Dansyl-4-aminophenylthio)-N-acetyl-9-O-acetylneuraminic Acid. A New Specific and Highly Sensitive Substrate in Sialate-O-Acetylesterase Assay

Zemplén Deacetylation

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