Thiamine analogues featuring amino-oxetanes as potent and selective inhibitors of pyruvate dehydrogenase
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved..
Pyruvate dehydrogenase complex (PDHc) is suppressed in some cancer types but overexpressed in others. To understand its contrasting oncogenic roles, there is a need for selective PDHc inhibitors. Its E1-subunit (PDH E1) is a thiamine pyrophosphate (TPP)-dependent enzyme and catalyses the first and rate-limiting step of the complex. In a recent study, we reported a series of ester-based thiamine analogues as selective TPP-competitive PDH E1 inhibitors with low nanomolar affinity. However, when the ester linker was replaced with an amide for stability reasons, the binding affinity was significantly reduced. In this study, we show that an amino-oxetane bioisostere of the amide improves the affinity and maintains stability towards esterase-catalysed hydrolysis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:98 |
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| Enthalten in: |
Bioorganic & medicinal chemistry letters - 98(2024) vom: 15. Jan., Seite 129571 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chan, Alex H Y [VerfasserIn] |
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| Links: |
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| Themen: |
Amides |
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| Anmerkungen: |
Date Completed 16.01.2024 Date Revised 16.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmcl.2023.129571 |
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| 520 | |a Pyruvate dehydrogenase complex (PDHc) is suppressed in some cancer types but overexpressed in others. To understand its contrasting oncogenic roles, there is a need for selective PDHc inhibitors. Its E1-subunit (PDH E1) is a thiamine pyrophosphate (TPP)-dependent enzyme and catalyses the first and rate-limiting step of the complex. In a recent study, we reported a series of ester-based thiamine analogues as selective TPP-competitive PDH E1 inhibitors with low nanomolar affinity. However, when the ester linker was replaced with an amide for stability reasons, the binding affinity was significantly reduced. In this study, we show that an amino-oxetane bioisostere of the amide improves the affinity and maintains stability towards esterase-catalysed hydrolysis | ||
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