Towards New Thymidine Phosphorylase/PD-ECGF Inhibitors Based on the Transition State of the Enzyme Reaction

Priego, Eva-Marı́a; Mendieta, Jesús; Gago, Federico; Balzarini, Jan; Clercq, Erik De; Camarasa, Marı́a-José; Pérez-Pérez, M J

doi:10.1081/ncn-120022693

Cited by 4 publications

(3 citation statements)

References 2 publications

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“…Unlike most N-ribosyl transferases, the arsenolysis reaction catalyzed by TP has a near-symmetrical nucleophilic displacement that characterizes its transition state [24]. Although this conclusion has been disputed by computational proposals [25][26][27], there is no other logical interpretation for the large (13.9%) [1'- 14 C]thymidine kinetic isotope effect [24,28]. A remote kinetic isotope effect for the [5'-3 H 2 ]thymidine was 6.1%, similar to that reported earlier for nucleoside hydrolase and attributed to a BIE [17,28].…”

Section: Thymidine Phosphorylasementioning

confidence: 99%

Binding isotope effects: boon and bane

Schramm

2007

Current Opinion in Chemical Biology

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Kinetic isotope effects are increasingly applied to investigate enzyme reactions and have been used to understand transition state structure, reaction mechanisms, quantum mechanical hydride ion tunneling and to design transition state analogue inhibitors. Binding isotope effects are an inherent part of most isotope effect measurements but are usually assumed to be negligible. More detailed studies have established surprisingly large binding isotope effects with lactate dehydrogenase, hexokinase, thymidine phosphorylase, and purine nucleoside phosphorylase. Binding reactants into catalytic sites immobilizes conformationally flexible groups, polarizes bonds, and distorts bond angle geometry, all of which generate binding isotope effects. Binding isotope effects are easily measured and provide high-resolution and detailed information on the atomic changes resulting from ligand-macromolecular interactions. Although binding isotope effects complicate kinetic isotope effect analysis, they also provide a powerful tool for finding atomic distortion in molecular interactions.

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Section: Thymidine Phosphorylasementioning

confidence: 99%

Binding isotope effects: boon and bane

Schramm

2007

Current Opinion in Chemical Biology

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“…The enzymatic synthesis of both natural and unnatural nucleosides reported in the last two decades, offers In addition, NPs present a biomedical interest due to their key role in nucleoside metabolism mainly in cancer chemotherapies [33].…”

Section: Introduction a General Aspectsmentioning

confidence: 99%

Nucleoside Phosphorylases

Lewkowicz

Iribarren

2006

COC

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Nucleoside phosphorylases (NPs) are transferases that catalyse the reversible cleavage of the glycosidic bond of ribo-or deoxyribo nucleosides, in the presence of inorganic phosphate, to generate the base and ribose-or deoxyribose-1-phosphate.Since pyrimidine as well as purine nucleoside phosphorylases exist, the combination of both enzymes makes possible the generation of purine nucleosides from pyrimidine ones. As a consequence, NPs from different sources, mainly bacterial, have been exploited as tools for the enzymatic synthesis of nucleoside analogues. These molecules are extensively used as antiviral and anticancer agents because of their ability to act as reverse transcriptase inhibitors or chain terminators in RNA or DNA synthesis.This review covers literature reports from 2000 on, focused mainly on the synthesis of nucleosides by free and immobilised microbial whole cells, along with some examples of modified nucleosides obtained by coupling transglycosylation to other enzymatic reactions.The biological aspects of NPs are also discussed since they became an interesting target for clinical applications due to their key role in nucleotide metabolism. Finally, brief comments about their structures and catalytic mechanisms are included.

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“…In recent years, a number of TP inhibitors have been synthesised ( Figure 3). These include the 5-and 6-substituted uracil analogues (e.g., 6-amino-5-bromouracil (10, 6A5BU)) (Langen et al 1967;Pan et al 1998), multi-substrate alkylphosphonates (11, Y = alkyl chain) (Esteban-Gamboa et al 2000), transition-state analogues (Priego et al 2003) and the methylene-bridged bicyclic compounds of type 12 (Klein et al 2001;Murray et al 2002;Yano et al 2004a, b). Prodrugs of inhibitors of TP have also been synthesised in which 2nitroimidazolyluracil prodrugs (13) require bioactivation under tumour conditions to form the active species, 2′aminoimidazolyluracils (14) (Cole et al 2003;Reigan et al 2004Reigan et al , 2005.…”

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confidence: 99%

Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

McNally

Rajabi

Gbaj

et al. 2007

Journal of Pharmacy and Pharmacology

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A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low muM range. The absence of a methylene bridge between the uracil and the imidazolyl subunits (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding.

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Towards New Thymidine Phosphorylase/PD-ECGF Inhibitors Based on the Transition State of the Enzyme Reaction

Cited by 4 publications

References 2 publications

Binding isotope effects: boon and bane

Binding isotope effects: boon and bane

Nucleoside Phosphorylases

Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

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