Branched montbretin A mimics allow derivatisation and potent amylase inhibition

Mimics of the complex flavonol glycoside montbretin A in which a flavonol moiety is coupled to a caffeic acid via partially peptidic linkers have proved to be potent inhibitors of human pancreatic alpha-amylase with potential as therapeutics for control of blood glucose levels. After exploring optim...

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Veröffentlicht in:Organic & biomolecular chemistry 2023-10, Vol.21 (39), p.7977-7983
Hauptverfasser: Calvert, Matthew, Sweeney, Ryan P, Chen, Hong-Ming, Bajwa, Harbir, Nasseri, Seyed A, Habibi, Davood, Withers, Stephen G
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Sprache:eng
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Zusammenfassung:Mimics of the complex flavonol glycoside montbretin A in which a flavonol moiety is coupled to a caffeic acid via partially peptidic linkers have proved to be potent inhibitors of human pancreatic alpha-amylase with potential as therapeutics for control of blood glucose levels. After exploring optimal linker length, a synthetic route to a version with a branched linker was devised based on the structure of the enzyme/inhibitor complex. The resultant branched inhibitors were shown to retain nanomolar potency even when decorated with polymers as a means of modifying solubility. Similar improvements, along with nanomolar affinity, could also be achieved through conjugation to cyclodextrins which have the potential to bind to starch binding sites found on the surface of human amylase. Incorporation of a conjugatable branch into this unusual pharmacophore thereby affords considerable flexibility for further modifications to improve pharmacokinetic behaviour or as a site for attachment of capture tags or fluorophores. Structure-based design of a branched version of a high affinity amylase inhibitor based on the natural product montbretin A allows derivatization and manipulation of physical properties while retaining potent (nM) inhibition.
ISSN:1477-0520
1477-0539
DOI:10.1039/d3ob01051a