Abstract
The design, synthesis and application of N-acetylneuraminic acid-derived compounds bearing anomeric sulfo functional groups are described. These novel compounds, which we refer to as sulfo-sialic acid analogues, include 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid and its 4-deoxy-3,4-dehydrogenated pseudoglycal. While 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid contains no further modifications of the 2-deoxy-pyranose ring, it is still a more potent inhibitor of avian-origin H5N1 neuraminidase (NA) and drug-resistant His275Tyr NA as compared to the oxocarbenium ion transition state analogue 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. The sulfo-sialic acid analogues described in this report are also more potent inhibitors of influenza NA (up to 40-fold) and bacterial NA (up to 8.5-fold) relative to the corresponding anomeric phosphonic acids. These results confirm that this novel anomeric sulfo modification offers great potential to improve the potency of next-generation NA inhibitors including covalent inhibitors.
Highlights
Replacement of the inhibitor carboxy group with a phosphono group has previously been reported to improve NA inhibitory activity and phosphonic acid analogues of sialic acid are currently under development[4,5,6,7,8,9,10]
Based upon the higher acidity and electronegativity of sulfo relative to carboxy and phosphono functional groups, we predicted that sialic acid anomeric sulfonic acid analogues, which we refer to as sulfo-sialic acid analogues, should form the strongest electrostatic interactions with the conserved NA active site triarginyl cluster (Fig. 1)
We first became interested in the synthesis of sulfo-sialic acid analogues during our research on covalent NA inhibitors, which have utilized an electronegative 3-fluoro group to destabilize formation of oxocarbenium ion transition states (Fig. 1A)[3]
Summary
Replacement of the inhibitor carboxy group with a phosphono group has previously been reported to improve NA inhibitory activity and phosphonic acid analogues of sialic acid are currently under development[4,5,6,7,8,9,10]. We first became interested in the synthesis of sulfo-sialic acid analogues during our research on covalent NA inhibitors, which have utilized an electronegative 3-fluoro group to destabilize formation of oxocarbenium ion transition states (Fig. 1A)[3].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
