Inhibition of human thymidine phosphorylase by conformationally constrained pyrimidine nucleoside phosphonic acids and their "open-structure" isosteres.
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.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Ivana
I
Košiová
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Ondřej
O
Šimák
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Natalya
N
Panova
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Miloš
M
Buděšínský
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Magdalena
M
Petrová
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Dominik
D
Rejman
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Radek
R
Liboska
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic.
Ondřej
O
Páv
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic. Electronic address: rosenberg@uochb.cas.cz.
Ivan
I
Rosenberg
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D010757:Phosphorous Acids / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010757:Phosphorous Acids; D011741:Pyrimidine Nucleosides; D013939:Thymidine Phosphorylase
Bi-substrate-like inhibitor; Conformationally constrained nucleotide analog; Human thymidine phosphorylase; Michael addition; PBMC; Phosphonate