Structural diversity of nucleoside phosphonic acids as a key factor in the discovery of potent inhibitors of rat T-cell lymphoma thymidine phosphorylase.
Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC(50) values below 1 microM were selected. Out of them, four compounds strongly inhibited the enzyme with IC(50) values lying in a range of 11-45 nM. These most potent compounds might be bi-substrate analogues.
Kocalka
Petr
P
Institute of Organic Chemistry and Biochemistry, Academy of Sciences vvi, Flemingovo 2, 166 10 Prague 6, Czech Republic.
Rejman
Dominik
D
Vanek
Václav
V
Rinnová
Markéta
M
Tomecková
Ivana
I
Králíková
Sárka
S
Petrová
Magdalena
M
Páv
Ondrej
O
Pohl
Radek
R
Budesínský
Milos
M
Liboska
Radek
R
Tocík
Zdenek
Z
Panova
Natalya
N
Votruba
Ivan
I
Rosenberg
Ivan
I
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D016399:Lymphoma, T-Cell / Q000201:enzymology*; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D009705:Nucleosides; D063065:Organophosphonates; D013939:Thymidine Phosphorylase