Synthesis of Novel Pyridine‐Carboxylates as Small‐Molecule Inhibitors of Human Aspartate/Asparagine‐β‐Hydroxylase
Abstract: The human 2‐oxoglutarate (2OG)‐dependent oxygenase aspartate/asparagine‐β‐hydroxylase (AspH) is a potential medicinal chemistry target for anticancer therapy. AspH is present on the cell surface of invasive cancer cells and accepts epidermal growth factor‐like domain (EGFD) substrates with a noncanonical (i. e., Cys 1–2, 3–4, 5–6) disulfide pattern. We report a concise synthesis of C‐3‐substituted derivatives of pyridine‐2,4‐dicarboxylic acid (2,4‐PDCA) as 2OG competitors for use in SAR studies on AspH inhibition. AspH inhibition was assayed by using a mass spectrometry‐based assay with a stable thioether analogue of a natural EGFD AspH substrate. Certain C‐3‐substituted 2,4‐PDCA derivatives were potent AspH inhibitors, manifesting selectivity over some, but not all, other tested human 2OG oxygenases. The results raise questions about the use of pyridine‐carboxylate‐related 2OG analogues as selective functional probes for specific 2OG oxygenases, and should aid in the development of AspH inhibitors suitable for in vivo use.
- Location
-
Deutsche Nationalbibliothek Frankfurt am Main
- Extent
-
Online-Ressource
- Language
-
Englisch
- Bibliographic citation
-
Synthesis of Novel Pyridine‐Carboxylates as Small‐Molecule Inhibitors of Human Aspartate/Asparagine‐β‐Hydroxylase ; volume:15 ; number:13 ; year:2020 ; pages:1139-1149 ; extent:11
ChemMedChem ; 15, Heft 13 (2020), 1139-1149 (gesamt 11)
- Creator
-
Brewitz, Lennart
Tumber, Anthony
Thalhammer, Armin
Salah, Eidarus
Christensen, Kirsten E.
Schofield, Christopher
- DOI
-
10.1002/cmdc.202000147
- URN
-
urn:nbn:de:101:1-2022062513374061305336
- Rights
-
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
-
15.08.2025, 7:35 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Brewitz, Lennart
- Tumber, Anthony
- Thalhammer, Armin
- Salah, Eidarus
- Christensen, Kirsten E.
- Schofield, Christopher