- Publikační typ
- abstrakt z konference MeSH
A series of new monophosphates of 1-[2-(phosphonomethoxy)alkyl]thymines, such as PMPTp(,) 3-MeO-PMPTp, HPMPTp, and FPMPTp, were synthesized and tested for their ability to inhibit human thymidine phosphorylase. Kinetic measurements of enzyme activity were performed using thymidine and inorganic phosphate as the substrates. The data show that some monophosphates provide a considerable increase of the multisubstrate inhibitory effect. The highest inhibitory potency was found with (R)-FPMPTp 4c (K (i) (dT) = 4.09 ± 0.47 μM, K (i)(P(i)) = 2.13 ± 0.29 μM) and (R) 3-MeO-PMPTp 4d (K (i) (dT) = 5.78 ± 0.71 μM, K (i)(P(i)) = 2.71 ± 0.37 μM).
- MeSH
- Cricetulus MeSH
- fosfáty MeSH
- fosforylace MeSH
- kinetika MeSH
- křečci praví MeSH
- kyseliny fosforité chemická syntéza chemie metabolismus farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- thymidin MeSH
- thymidinfosforylasa antagonisté a inhibitory MeSH
- thymin analogy a deriváty chemická syntéza chemie metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The structure-activity study on the phosphates of phosphonomethoxypropyl derivatives of purine bases interacting with human purine nucleoside phosphorylase has shown that the most efficient inhibitors of the enzyme are (R)- and (S)-PMPGp with Ki ~ 1.9 × 10–8 and/or 2.2 × 10–8 mol/l. The kinetic experiments have proven, with the exception of both enantiomers of PMP-8-BrDAPp, strictly competitive character of inhibition for all ANP monophosphates tested. Bromine derivatives exhibited uncompetitive and mixed type of inhibition as well. These results were confirmed by docking studies. The substitution of purine moiety with the bromine at the position 8 lead to an allosteric binding of these compounds toward the enzyme.
Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibit significant inhibitory activity against this enzyme. The most potent compounds bear a five- or six-membered cyclic substituent containing a pi-electron system at C5 and a chlorine atom attached at C6. 6-Chloro-5-cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with Ki = 0.20 +/- 0.03 microM (Ki/dThdKm = 0.0017) for thymidine phosphorylase expressed in V79 cells and Ki = 0.29 +/- 0.04 microM (Ki/dThdKm = 0.0024) for the enzyme purified from placenta.
We report on a series of novel 5,6-disubstituted uracils with significant inhibitory activity against human and Escherichia coli thymidine phosphorylases. Bis-uracil conjugates were identified as the most potent inhibitors of TPs in this study.
- MeSH
- aminy chemie MeSH
- Escherichia coli enzymologie účinky léků MeSH
- financování organizované MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory enzymů farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv MeSH
- thymidinfosforylasa antagonisté a inhibitory metabolismus MeSH
- uracil analogy a deriváty farmakologie chemická syntéza chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- MeSH
- adenin analogy a deriváty farmakologie metabolismus MeSH
- antitumorózní látky metabolismus MeSH
- guanin analogy a deriváty metabolismus MeSH
- izoenzymy analogy a deriváty metabolismus MeSH
- kinetika MeSH
- nukleosidmonofosfátkinasa antagonisté a inhibitory metabolismus MeSH
- organofosforové sloučeniny metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
