Inhibition of human thymidine phosphorylase by conformationally constrained pyrimidine nucleoside phosphonic acids and their "open-structure" isosteres

0428628 - ÚOCHB 2015 RIV FR eng J - Journal Article
Markusová Kóšiová, Ivana - Šimák, Ondřej - Panova, Natalya - Buděšínský, Miloš - Petrová, Magdalena - Rejman, Dominik - Liboska, Radek - Páv, Ondřej - Rosenberg, Ivan
Inhibition of human thymidine phosphorylase by conformationally constrained pyrimidine nucleoside phosphonic acids and their "open-structure" isosteres.
European Journal of Medicinal Chemistry. Roč. 74, Mar 3 (2014), s. 145-168. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR GA203/09/0820; GA ČR GA202/09/0193; GA ČR GA13-24880S; GA ČR GA13-26526S
Institutional support: RVO:61388963
Keywords : phosphonate * conformationally constrained nucleotide analog * human thymidine phosphorylase * PBMC * bi-substrate-like inhibitor * Michael addition
Subject RIV: CC - Organic Chemistry
Impact factor: 3.447, year: 2014

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 K-i values in the range of 0.048-1 mu M. The inhibition potency of the studied compounds strongly depended on the degree of conformational flexibility of the phosphonate moiety, the stereochemical arrangement of the sugarphosphonate component, and the substituent at position 5 of the pyrimidine nucleobase.
Permanent Link: http://hdl.handle.net/11104/0233950