The radioactively labelled 6-amino-5-nitroso-uracil (1) and 5-acetyl-6-amino-1,3-dimethyl-uracil (2) were required for metabolic studies to assess their suitability as drug candidates. A common precursor for both compounds was [cyano-14 C]cyanoacetic acid (6), readily prepared from potassium [14 C]cyanide. ACS reagents, namely, diethyl ether, acetic acid and acetic anhydride, had to be rigorously repurified to achieve a successful synthesis of 14 C-labelled compounds on a tenth-of-a-milligramme scale. 6-Amino-5-nitroso-[6-14 C]uracil (1-14 C) (0.55 mCi) was prepared with radiochemical purity > 98% and specific activity (SA) = 55.6 mCi/mmol. 5-Acetyl-6-amino-1,3-dimethyl-[6-14 C]uracil (2-14 C) (8 mCi) was prepared with radiochemical purity > 97% and SA = 55.6 mCi/mmol. It has been shown that a SA assay can be made from standard 13 C NMR spectra, thus avoiding the need to perform lengthier inverse-gated 13 C NMR experiments.
A number of 5-alkoxymethyluracil analogues were synthesized to evaluate their cytotoxic activity. 5-Alkoxymethyluracil derivatives 1 were prepared via known nucleophilic substitution of 5-chloromethyluracil 5 and subsequently transformed to their corresponding nucleosides 2. All prepared compounds were submitted to cytotoxic activity testing against drug sensitive and drug resistant leukaemia cells and solid tumour derived cell lines. In addition, the cytotoxic activity of 5-alkoxymethyluracil analogues 1 and 2 was compared with the previously published 5-[alkoxy(4-nitrophenyl)methyl]uracil analogues 3 and 4. Extensive structure-cytotoxic activity relationship studies are reported.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- uracil analogy a deriváty chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The preparation of various 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils with alkyl chain lengths C(1)-C(12) is described. The synthesis is based on the preparation of 5-[chloro-(4-nitro-phenyl)-methyl]-uracil and subsequent substitution of chlorine with appropriate alcohols. The resulting ethers were tested for their cytotoxic activity in vitro against five cancer cell lines. The compounds were less active in lung resistance protein expressing cell lines, suggesting the involvement of this multidrug resistant protein in control of the biological activity. Cytotoxic substances induced rapid inhibition of DNA and modulation of RNA synthesis followed by induction of apoptosis. The data indicate that the biological activity of 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils depends on the alkyl chain length.
- MeSH
- alkoholy chemická syntéza toxicita MeSH
- antitumorózní látky chemická syntéza toxicita MeSH
- buňky K562 MeSH
- cytotoxiny chemická syntéza toxicita MeSH
- financování organizované MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- stereoizomerie MeSH
- uracil analogy a deriváty chemická syntéza toxicita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
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
- uracil chemická syntéza MeSH
