Conformationally constrained nucleoside phosphonic acids--potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25178098
DOI
10.1039/c4ob01332h
Knihovny.cz E-resources
- MeSH
- 5'-Nucleotidase antagonists & inhibitors metabolism MeSH
- Cytosol enzymology MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Mitochondria enzymology MeSH
- Molecular Conformation MeSH
- Organophosphonates chemical synthesis chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 5'-Nucleotidase MeSH
- 5'(3')-nucleotidase MeSH Browser
- Enzyme Inhibitors MeSH
- Organophosphonates MeSH
This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-d-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K = 2.71 μM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K = 6.60 μM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy.
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