Inhibition of human thymidine phosphorylase by conformationally constrained pyrimidine nucleoside phosphonic acids and their "open-structure" isosteres
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
24462848
DOI
10.1016/j.ejmech.2013.12.026
PII: S0223-5234(13)00814-3
Knihovny.cz E-zdroje
- Klíčová slova
- Bi-substrate-like inhibitor, Conformationally constrained nucleotide analog, Human thymidine phosphorylase, Michael addition, PBMC, Phosphonate,
- MeSH
- inhibitory enzymů farmakologie MeSH
- kyseliny fosforité chemie farmakologie MeSH
- lidé MeSH
- molekulární konformace MeSH
- pyrimidinové nukleosidy farmakologie MeSH
- thymidinfosforylasa antagonisté a inhibitory MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- inhibitory enzymů MeSH
- kyseliny fosforité MeSH
- pyrimidinové nukleosidy MeSH
- thymidinfosforylasa MeSH
A series of conformationally constrained uridine-based nucleoside phosphonic acids containing annealed 1,3-dioxolane and 1,4-dioxane rings and their "open-structure" isosteres were synthesized and evaluated as potential multisubstrate-like inhibitors of the human recombinant thymidine phosphorylase (TP, EC 2.4.2.4) and TP obtained from peripheral blood mononuclear cells (PBMC). From a large set of tested nucleoside phosphonic acids, several potent compounds were identified that exhibited Ki values in the range of 0.048-1 μM. The inhibition potency of the studied compounds strongly depended on the degree of conformational flexibility of the phosphonate moiety, the stereochemical arrangement of the sugar-phosphonate component, and the substituent at position 5 of the pyrimidine nucleobase.
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