51-21-8Relevant academic research and scientific papers
Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase
Shea, Tara A.,Burburan, Paola J.,Matubia, Vivian N.,Ramcharan, Sandy S.,Rosario Jr., Irving,Parkin, David W.,Stockman, Brian J.
, p. 1080 - 1084 (2014)
Trichomonas vaginalis continues to be a major health problem with drug-resistant strains increasing in prevalence. Novel antitrichomonal agents that are mechanistically distinct from current therapies are needed. The NIH Clinical Compound Collection was screened to find inhibitors of the uridine ribohydrolase enzyme required by the parasite to scavenge uracil for its growth. The proton-pump inhibitors omeprazole, pantoprazole, and rabeprazole were identified as inhibitors of this enzyme, with IC50 values ranging from 0.3 to 14.5 μM. This suggests a molecular mechanism for the in vitro antitrichomonal activity of these proton-pump inhibitors, and may provide important insights toward structure-based drug design.
Synthesis and drug release in vitro of porphyran carrying 5-Fluorouracil
Zhang, Zhongshan,Zhang, Quanbin,Wang, Jing,Shi, Xuelian,Zhang, Jingjing,Song, Houfang
, p. 628 - 632 (2010)
Porphyran, the sulfated polysaccharide from red algae Porphyra haitanensis, possesses excellent bioactivities, especially the immune activity. In order to provide a water-soluble macromolecule prodrug of 5-FU showing slow release of 5-FU, reducing side-effect, we employed porphyran as a drug carrier, and carried out fixation of 5-FU to porphyran at 6-position through acetyl spacer group via ester bond. The chemical characteristic and release behavior of 5-FU from the conjugate obtained were studied in vitro at 37 °C in three different medium. The results represented that the release mechanism of all the conjugates was a typical Fickian diffusion. However, further in vivo studies on animal models are necessary to establish the efficiency of the system.
Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach
Cherukaraveedu, Durgadas,Cowling, Paul T.,Birch, Gavin P.,Bradley, Mark,Lilienkampf, Annamaria
, p. 5533 - 5537 (2019)
Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.
A convenient synthesis of 5-fluoropyrimidines using 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)-SELECTFLUOR reagent
Lal,Pastore,Pesaresi
, p. 7340 - 7342 (1995)
The pyrimidine bases uracil and thymine react with the titled reagent in water to generate the corresponding fluorohydrins. Uracil fluorohydrin provides 5-fluorouracil on sublimation. Triacetyluridine reacts similarly in the presence of H2O, AcOH, or MeOH to form the respective adducts from which 5-fluorotriacetyluridine was obtained. The fluorohydrin of diacetylthymidine and the difluoromethoxy derivative of triacetylcytidine were also obtained by reaction of the nucleosides with 1-(chloromethyl)-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate)-SELECTFLUOR in H3O and MeOH, respectively. This method represents a new practical and direct route to 5-fluoropyrimidine nucleoside.
Stereoelectronic effect on one-electron reductive release of 5-Fluorouracil from 5-fluoro-1-(2'-oxocycloalkyl)uracils as a new class of radiation-activated antitumor prodrugs
Mori, Mayuko,Hatta, Hiroshi,Nishimoto, Sei-Ichi
, p. 4641 - 4647 (2000)
A series of 5-fluoro-1-(2'-oxocycloalkyl)uracils (3-11) that are potentially novel radiation-activated prodrugs for the radiotherapy of hypoxic tumor cells have been synthesized to evaluate a relationship between the molecular structure and the reactivity of one-electron reductive release of antitumor 5-fluorouracil (1) in anoxic aqueous solution. All the compounds 3-11 bearing the 2'-oxo group were one-electron reduced by hydrated electrons (e(aq)-) and thereby underwent C(1')-N(1) bond dissociation to release 5-fluorouracil 1 in 47-96% yields upon radiolysis of anoxic aqueous solution, while control compounds (12, 13) without the 2'-oxo substituent had no reactivity toward such a reductive C(1')-N(1) bond dissociation. The decomposition of 2-oxo compounds in the radiolytic one-electron reduction was more enhanced, as the one-electron reduction potential measured by cyclic voltammetry in N,N-dimethylformamide became more positive. The efficiency of 5-fluorouracil release was strongly dependent on the structural flexibility of 2-oxo compounds. X-ray crystallographic studies of representative compounds revealed that the C(1')-N(1) bond possesses normal geometry and bond length in the ground state. MO calculations by the AM1 method demonstrated that the LUMO is primarily localized at the π* orbital of C(5)-C(6) double bond of the 5-fluorouracil moiety, and that the LUMO + 1 is delocalized between the π* orbital of 2'-oxo substituent and the σ* orbital of adjacent C(1')-N(1) bond. The one-electron reductive release of 5-fluorouracil 1 in anoxic aqueous solution was presumed to occur from the LUMO + 1 of radical anion intermediates possessing a partial mixing of the antibonding C(2')=O π* and C(1')-N(1) σ(*) MO's, that may be facilitated by a dynamic conformational change to achieve higher degree of (π + σ) MO mixing.
Electron spin resonance of gamma- and X irradiated nucleic acid base pairs. 1 Methylcytosine: 5 fluorouracil co crystals at 77°K
Farley,Bernhard
, p. 47 - 54 (1975)
The predominant free radical trapped in single crystals of a hydrogen bonded complex of 1 methylcytosine and 5 fluorouracil x irradiated between 77°K and room temperature has been identified. It is characterized by hydrogen atom extraction from N(1) of the 5 fluorouracil moiety, the unpaired electron interacting with the N(1) and F nuclei of this molecule. The principal values of the hyperfine and g tensors are given. The radical is present at 77°K and decays upon warming to room temperature. There is at least one additional radical present at 77°K, but its structure has not been determined.
5-fluoro-5-halo- and 5-fluoro-5-nitro-substituted uracil derivatives. synthesis and structure
Chernikova, Inna B.,Khursan, Sergey L.,Spirikhin, Leonid V.,Yunusov, Marat S.
, p. 568 - 572 (2015)
[MediaObject not available: see fulltext.] 5-Bromo-5-fluoro- and 5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracils were obtained in high yields by oxidative halogenation of 5-fluorouracil. Nitration of 5-fluorouracil gave 5-fluoro-6-hydroxy-5-nitro-5,6-dihydrouracil. Theoretical calculations in B3LYP/6-311+G(d,p) // B3LYP/6-311G(d,p) + IEFPCM approximation and GIAO simulation of 13C NMR spectra and spin-spin coupling constants agree with the structure of the compounds obtained, which manifest an equatorial orientation of the fluorine atom and an axial orientation of the hydroxy group at position 6 of the dihydrouracil ring. The principal possibility of oxidative iodination of 5-halouracils was studied in B3LYP/CEP-121G approximation. It was found that reversible elimination of iodine by a nucleophilic agent to give the original compounds is the main transformation pathway of the intermediate in this process.
Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclothymidine in tumor cell homogenates
Hamada, Akinobu,Nakano, Masahiro,Shimidzu, Satoshi,Hasegawa, Tetsuya,Kawaguchi, Takeo
, p. 935 - 938 (1997)
The inhibitory effect of acyclothymidine[AcyT, 5-methyl-1-(2'- hydroxyethoxymethyl) uracil], a potent pyrimidine nucleoside phosphorylase (PyNPase) inhibitor, on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in human and mouse tumor cell homogenates was measured. Competitive inhibition was observed in MKN-74 and Lewis lung carcinoma (LLC), whereas non- competitive inhibition was observed in HeLa. The strength of the inhibitory effect by AcyT showed the following pattern: HeLahuman normal intestinemouse normal intestineColon 26LLCMKN-74DLD-1. From the kinetic parameter obtained, we simulated the inhibitory effect of AcyT on 5'-DFUR phosphorolysis in tumor cells and the intestine. These data indicated that AcyT was more sensitive in normal mouse intestine than in Colon 26 find LLC, and that orally administered AcyT can reduce the intestinal toxicity of 5'- DFUR without reducing the antitumor effect in the mouse. The present finding may have an important implication for attempts to introduce AcyT, a potent PyNPase inhibitor, into the clinic.
Novel isoxazolidine analogues of homonucleosides and homonucleotides
Piotrowska, Dorota G.,Balzarini, Jan,Andrei, Graciela,Schols, Dominique,Snoeck, Robert,Wróblewski, Andrzej E.,Gotkowska, Joanna
, p. 8294 - 8308 (2016)
Isoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones 20a-20e (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl- and vinyloxymethyl- and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28–82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 μM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC50= ≥100 μM).
Inhibition of 5'-deoxy-5-flourouridine phospholysis by acyclopyrimidinenucleosides in intestinal tissue homogenates
Hamada,Fukushima,Saneyoshi,Kawaguchi,Nakano
, p. 172 - 175 (1995)
This study examined the inhibitory effect of acyclopyrimidinenucleosides on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in intestinal tissue derived from rabbit, rat, mouse, and human. 5-Bromoacyclouridine, 5-fluoroacyclouridine, acyclouridine, and 5-nitroacyclouridine showed little or only moderate effect, but acyclothymidine [5-methyl-1-(2'-hydroxyethoxymethyl)uracil] showed strong inhibitory effect on 5'-DFUR phosphorolysis in intestinal tissue homogenates derived from human. In the absence of inhibitor (acyclothymidine), the V(max) of 5'-DFUR phosphorolysis was 2.66 μmol/min and the K(m) was 0.57 mM in human intestinal homogenates. The V(max) was unaltered by increased inhibitor concentration. The maximal inhibitory effect of acyclothymidine on 5'-DFUR phosphorolysis in rat homogenates was over 90%. The K(i)/K(m) was 0.63 in human, 2.14 in rabbit, 1.09 x 10-2 in rat, and 1.71 x 10-2 in mouse. These data show that acyclothymidine is a competitive inhibitor of 5'-DFUR phosphorolysis, and that it can inhibit not only uridine phosphorylase but also thymidine phosphorylase.
