The synthesis of a series of deoxygenated 2,3-difluoro-N-acteylneuraminic acid derivatives as potential sialidase inhibitors

Hader, Stefan; Watts, Andrew G.

doi:10.1016/j.carres.2013.03.026

Cited by 12 publications

(19 citation statements)

References 29 publications

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“…Compounds 3−6 were prepared as previously described. 10 The purity of final compounds was ≥95%. Purity was determined by elemental analysis and is available in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the 4-amino and 4-guanidino derivatives of 2, we have now synthesized a series of deoxygenated DFSA derivatives 3−6 (Figure 1) in order to understand the contribution of each hydroxyl in binding and inhibition of these sialic acid based inhibitors to the influenza NA. 10 The influenza strains selected for evaluating the impact of removal of the OH groups were those of clinical importance to humans, including the endemic human strains seasonal A(H1N1), pandemic (H1N1)pdm09, A(H3N2) and B, and avian A(H5N1) and the A(H1N9) reassortant, as a model for the avian A(H7N9) NA. NAI resistant mutants of some of these viruses, with different resistance profiles, were also used in the enzyme assays.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro-N-acetylneuraminic Acid Derivatives

et al. 2018

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Competitive inhibitors of the influenza neuraminidase (NA) were discovered almost 20 years ago, with zanamivir and oseltamivir licensed globally. These compounds are based on a transition state analogue of the sialic acid substrate. We recently showed that 5- N-(acetylamino)-2,3,5-trideoxy-2,3-difluoro-d-erythro-β-l-manno-2-nonulopyranosonic acid (DFSA) and its derivatives are also potent inhibitors of the influenza NA. They are mechanism based inhibitors, forming a covalent bond between the C2 of the sugar ring and Y406 in the NA active site, thus inactivating the enzyme. We have now synthesized a series of deoxygenated DFSA derivatives in order to understand the contribution of each hydroxyl in DFSA to binding and inhibition of the influenza NA. We have investigated their relative efficacy in enzyme assays in vitro, in cell culture, and by X-ray crystallography. We found loss of the 8- and 9-OH had the biggest impact on the affinity of binding and antiviral potency.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro-N-acetylneuraminic Acid Derivatives

et al. 2018

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“…To the best of our knowledge, this might be the only example of synthesis of a C‐4 modified sialoconjugate by an enzyme to date. In addition, Watts and co‐worker recently reported the synthesis of a series of mono‐deoxygenated sialic acid derivatives, including 4‐deoxy‐Neu5Ac, using Barton–McCombie deoxygenations, in order to investigate sialidase mechanisms 126…”

Section: Syntheses With Modified Sialosidesmentioning

confidence: 99%

Recent Developments in Enzymatic Synthesis of Modified Sialic Acid Derivatives

Withers

2015

Adv Synth Catal

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Sialic acid-containing glycans play important roles in biology, but their synthesisb ys tandard chemical approaches is challenging. Enzymatic assemblyi sg enerally ab etter approach. In the last two decades,anumber of bacterial sialyltransferases (STs) and trans-sialidasesh ave been identifieda nd an umber of them found to exhibit broad substrate specificity.I nt his review,w ew illf ocuso nt he donor and acceptor substrate specificities of these enzymes along with the enzymatic routes employed to prepare sialosidesb earing modificationsa ts pecific positions on the sialic acid carbon skeleton. Understanding the substrate tolerance of these enzymes will help researchers to choose the best biocatalyst for the assemblyo fs pecific sialosides,w hich can be valuable tools in the study of or inhibition of sialidases and STs and sialica cid-binding proteins.I na ddition,t he ability to study these processes using synthetic sialylated glycans will leadt oagreater understanding of their biologya nd willl ead to newt herapeutic targets.1I ntroduction 2S ialic AcidsinN ature 3S ynthesis of Sialic Acid-ContainingO ligosaccharides 4B acterial Sialyltransferases and trans-Sialidases 4

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“…Additionally, there is an interest in using these synthetic carbohydrate antigen fragments for the development of conjugate vaccines owing to their beneficial pharmacokinetic properties, such as enhanced metabolic stability8 and immunogenicity 9. Fluorinated analogues of sialic acids represent another promising application in medicinal chemistry as they are potential sialidase inhibitors and, therefore, may be used for the treatment of medical conditions such as viral infections, cancer, or diabetes 10. Another advantage of fluorine is the possibility to perform facile NMR‐based investigations 11.…”

Section: Introductionmentioning

confidence: 99%

Continuous Re‐hyperpolarization of Nuclear Spins Using Parahydrogen: Theory and Experiment

et al. 2014

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The continuous re-hyperpolarization of nuclear spins in the liquid state by means of parahydrogen (para-H2) and chemical exchange at low magnetic fields was recently discovered and offers intriguing perspectives for many varieties of magnetic resonance. In this contribution, we provide a theoretical assessment of this effect and compare the results to experimental data. A distinct distribution of polarization is found, which shares some features with experimental data and, interestingly, does not directly correspond to the loss of the singlet order of para-H2. We derived expressions for the magnetic field and para-H2-substrate interaction time, for which the polarization transfer is maximal. This work sheds light onto the effect of continuous hyperpolarization and elucidates the underlying mechanism, which may facilitate the development of an optimized catalyst. As an application, continuous hyperpolarization may enable highly sensitive nuclear magnetic resonance at very low magnetic fields, for example, for the cost-efficient screening of drugs.

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The synthesis of a series of deoxygenated 2,3-difluoro-N-acteylneuraminic acid derivatives as potential sialidase inhibitors

Cited by 12 publications

References 29 publications

Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro-N-acetylneuraminic Acid Derivatives

Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro-N-acetylneuraminic Acid Derivatives

Recent Developments in Enzymatic Synthesis of Modified Sialic Acid Derivatives

Continuous Re‐hyperpolarization of Nuclear Spins Using Parahydrogen: Theory and Experiment

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