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Facile and robust methods for the regioselective acylation of N-acetylneuraminic acid.

ABSTRACT: The stereoselective synthesis of sialic acid glycoconjugates is still a challenge in the field. Surprisingly, little is known on the regioselective O-substitution of sialic acids. Consequently, the effect of O-protecting groups and/or regioselectively protected building blocks in sialylations, remains practically unexplored. O-Picoloyl protecting groups have emerged as novel substituents that have a profound effect on sialylations. Recently, high stereoselectivities were obtained by introducing picoloyl groups at the C-4 and C-7/C-8 positions. However, to understand the relationship between the position of the picoloyl group and its exact effect in sialylations, a convenient access to a wider range of regioselectively picoloylated building blocks is needed. Reported herein is a new method that provides an accessible route to a wide array of regioselectively acylated building blocks. The regioselective introduction of picoloyl groups at various O-positions was achieved either by controlled direct picoloylation or by applying a modified ReSET methodology.

SUBMITTER: Shadrick M

PROVIDER: S-EPMC6104843 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Facile and robust methods for the regioselective acylation of N-acetylneuraminic acid.

Shadrick Melanie M Yu Charlene C Geringer Scott S Ritter Sean S Behm Alexanndra A Cox Abby A Lohman Matt M De Meo Cristina C

New journal of chemistry = Nouveau journal de chimie 20180717 17

The stereoselective synthesis of sialic acid glycoconjugates is still a challenge in the field. Surprisingly, little is known on the regioselective O-substitution of sialic acids. Consequently, the effect of O-protecting groups and/or regioselectively protected building blocks in sialylations, remains practically unexplored. O-Picoloyl protecting groups have emerged as novel substituents that have a profound effect on sialylations. Recently, high stereoselectivities were obtained by introducing ...[more]

PMID: 30147293

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Project description:N-Acetylneuraminic acid aldolase from Clostridium perfringens was irreversibly inactivated by 1mm-bromopyruvate with a half-life of 4.2min at pH7.2 and 37 degrees C. The rate of inactivation was diminished in the presence of pyruvate but not with N-acetyl-d-mannosamine, indicating that the inhibitor acted at, or close to, the pyruvate-binding site. The apparent K(i) for bromopyruvate, calculated from the variation of half-life with inhibitor concentration, was 0.46mm, compared with a competitive K(i) 3.0mm for pyruvate. Incubation of the enzyme with radioactive bromopyruvate gave a radioactive, enzymically inactive, protein in which the bromopyruvate had alkylated cysteine residues. Incubation of the enzyme with radioactive pyruvate, followed by reduction with sodium borohydride, led to inactivation of the enzyme and binding of the pyruvate to the protein by reduction of a Schiff's base initially formed with the in-amino group of a lysine residue; only one-twentieth as many pyruvyl residues were bound by this method, showing that bromopyruvate is not specific for the active site. After protection of the enzyme active site with pyruvate, treatment with unlabelled bromopyruvate and dialysis, the enzyme retained 72% activity. When this treated enzyme was separately incubated with radioactive bromopyruvate, or radioactive pyruvate followed by sodium borohydride, the ratio of radioactive pyruvyl residues bound by the two methods was 2.3:1. After reduction and hydrolysis of the bromopyruvate-treated enzyme, the only detectable radioactive amino acid derivative was chromatographically and electrophoretically identical with S-(3-lactic acid)-cysteine. The enzyme was fully active in the presence of EDTA and was not stimulated by bivalent metal ions. It was strongly inhibited by silver and mercuric ions. The apparent molecular weight, determined by Sephadex chromatography, was 250000. A mechanism of action is proposed for the enzyme. Bromopyruvate reacts rapidly at pH6.0 with thiol-containing amino acids. Cysteine appears to react anomalously.

Dataset Information

Facile and robust methods for the regioselective acylation of N-acetylneuraminic acid.

Publications

Facile and robust methods for the regioselective acylation of N-acetylneuraminic acid.

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