- Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase
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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.
- Shea, Tara A.,Burburan, Paola J.,Matubia, Vivian N.,Ramcharan, Sandy S.,Rosario Jr., Irving,Parkin, David W.,Stockman, Brian J.
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- Synthesis and drug release in vitro of porphyran carrying 5-Fluorouracil
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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.
- Zhang, Zhongshan,Zhang, Quanbin,Wang, Jing,Shi, Xuelian,Zhang, Jingjing,Song, Houfang
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- Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach
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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.
- Cherukaraveedu, Durgadas,Cowling, Paul T.,Birch, Gavin P.,Bradley, Mark,Lilienkampf, Annamaria
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- A convenient synthesis of 5-fluoropyrimidines using 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)-SELECTFLUOR reagent
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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.
- Lal,Pastore,Pesaresi
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- 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
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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.
- Mori, Mayuko,Hatta, Hiroshi,Nishimoto, Sei-Ichi
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- Electron spin resonance of gamma- and X irradiated nucleic acid base pairs. 1 Methylcytosine: 5 fluorouracil co crystals at 77°K
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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.
- Farley,Bernhard
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- 5-fluoro-5-halo- and 5-fluoro-5-nitro-substituted uracil derivatives. synthesis and structure
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[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.
- Chernikova, Inna B.,Khursan, Sergey L.,Spirikhin, Leonid V.,Yunusov, Marat S.
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- Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclothymidine in tumor cell homogenates
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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.
- Hamada, Akinobu,Nakano, Masahiro,Shimidzu, Satoshi,Hasegawa, Tetsuya,Kawaguchi, Takeo
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- Novel isoxazolidine analogues of homonucleosides and homonucleotides
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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).
- Piotrowska, Dorota G.,Balzarini, Jan,Andrei, Graciela,Schols, Dominique,Snoeck, Robert,Wróblewski, Andrzej E.,Gotkowska, Joanna
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- Inhibition of 5'-deoxy-5-flourouridine phospholysis by acyclopyrimidinenucleosides in intestinal tissue homogenates
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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.
- Hamada,Fukushima,Saneyoshi,Kawaguchi,Nakano
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- Kinetic Study on the γ-Radiolysis of 5-Fluorouracil Derivatives
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The reactivity of 5-fluoro-1-(2-phenylethenesulfonyl)uracil (1) and 5-fluoro-1-phenylthioureidouracil (2) in the γ-radiolysis of their aqueous solutions was studied by a competitive kinetic method using nitrobenzene and acetone as reference compounds.The rate constants for the reactions of 1 and 2 with eaq- were of the same order of magnitude as that for nitrobenzene.The efficiencies of the conversion of intermediates generated from 1 and 2 into 5-fluorouracil were also estimated.
- Kuroda, Tokuyuki,Hisamura, Koji,Nakamizo, Nobuhiro,Otsuji, Yoshio
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- Enzyme Architecture: Erection of Active Orotidine 5′-Monophosphate Decarboxylase by Substrate-Induced Conformational Changes
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Orotidine 5′-monophosphate decarboxylase (OMPDC) catalyzes the decarboxylation of 5-fluoroorotate (FO) with kcat/Km = 1.4 × 10-7 M-1 s-1. Combining this and related kinetic parameters shows that the 31 kcal/mol stabilization of the transition state for decarboxylation of OMP provided by OMPDC represents the sum of 11.8 and 10.6 kcal/mol stabilization by the substrate phosphodianion and the ribosyl ring, respectively, and an 8.6 kcal/mol stabilization from the orotate ring. The transition state for OMPDC-catalyzed decarboxylation of FO is stabilized by 5.2, 7.2, and 9.0 kcal/mol, respectively, by 1.0 M phosphite dianion, d-glycerol 3-phosphate and d-erythritol 4-phosphate. The stabilization is due to the utilization of binding interactions of the substrate fragments to drive an enzyme conformational change, which locks the orotate ring of the whole substrate, or the substrate pieces in a caged complex. We propose that enzyme-activation is a possible, and perhaps probable, consequence of any substrate-induced enzyme conformational change.
- Reyes, Archie C.,Amyes, Tina L.,Richard, John P.
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- Short oligonucleotide prodrug having 5-fluoro and 5-iodouracil inhibits the proliferation of cancer cells in a photo-responsive manner
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Photo-induced C1′ hydrogen abstraction of 5-fluoro-2′- deoxyuridine was adopted as the key reaction for releasing 5-fluorouracil (5-FU) anticancer drug from oligonucleotide strands. After photoirradiation following 5-FU release, anticancer activity was expected. We demonstrated that oligonucleotide tetramer, d(AFUIUA), can release 5-FU under physiological conditions in a photo-responsive manner thorough photo-induced C1′ hydrogen abstraction, and that the 5-FU released from d(AFUIUA) having a phosphorothioate backbone clearly suppresses the proliferation of HeLa cells in a photo-responsive manner.
- Fujimoto, Kenzo,Takematsu, Yu-Ki,Shigeno, Atsuo,Furusawa, Mirei,Sakamoto, Takashi
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- Click Nucleic Acid Mediated Loading of Prodrug Activating Enzymes in PEG-PLGA Nanoparticles for Combination Chemotherapy
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The simultaneous delivery of multiple therapeutics to a single site has shown promise for cancer targeting and treatment. However, because of the inherent differences in charge and size between drugs and biomolecules, new approaches are required for colocalization of unlike components in one delivery vehicle. In this work, we demonstrate that triblock copolymers containing click nucleic acids (CNAs) can be used to simultaneously load a prodrug enzyme (cytosine deaminase, CodA) and a chemotherapy drug (doxorubicin, DOX) in a single polymer nanoparticle. CNAs are synthetic analogs of DNA comprised of a thiolene backbone and nucleotide bases that can hybridize to complementary strands of DNA. In this study, CodA was appended with complementary DNA sequences and fluorescent dyes to allow its encapsulation in PEG-CNA-PLGA nanoparticles. The DNA-modified CodA was found to retain its enzyme activity for converting prodrug 5-fluorocytosine (5-FC) to active 5-fluorouracil (5-FU) using a modified fluorescent assay. The DNA-conjugated CodA was then loaded into the PEG-CNA-PLGA nanoparticles and tested for cell cytotoxicity in the presence of the 5-FC prodrug. To study the effect of coloading DOX and CodA within a single nanoparticle, cell toxicity assays were run to compare dually loaded nanoparticles with nanoparticles loaded only with either DOX or CodA. We show that the highest level of cell death occurred when both DOX and CodA were simultaneously entrapped and delivered to cells in the presence of 5-FC.
- Harguindey, Albert,Roy, Shambojit,Harris, Alexander W.,Fairbanks, Benjamin D.,Goodwin, Andrew P.,Bowman, Christopher N.,Cha, Jennifer N.
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- Atomically Conformal Metal Laminations on Plasmonic Nanocrystals for Efficient Catalysis
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Despite the enormous application potential, methods for conformal few-atomic-layer deposition on colloidal nanocrystals (NCs) are scarce. Similar to the process of lamination, we introduce a confine and shine strategy to homogeneously modify the different surface curvatures of plasmonic NCs with ultrathin conformal layers of diverse catalytic noble metals. This self-limited epitaxial skinlike metal growth harvests the localized surface plasmon resonance to induce reduction chemistry directly on the NC surface, confined inside hollow silica. This strategy avoids any kinetic anisotropic metal deposition. Unlike the conventional thick, anisotropic, and dendritic shells, which show severe nonradiative damping, the skinlike metal lamination preserves the key plasmonic properties of the core NCs. Consequently, the plasmonic-catalytic hybrid nanoreactors can carry out a variety of organic reactions with impressive rates.
- Acharya, Anubhab,Cho, Yoon-Kyoung,Dubbu, Sateesh,Kim, Yeseul,Kumar, Amit,Kumar, Sumit,Kumari, Nitee,Kwon, Taewan,Lee, In Su,Oh, Sang Ho,Park, Junbeom,Rho, Junsuk,So, Sunae,Wang, Zhipeng
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supporting information
p. 10582 - 10589
(2021/07/26)
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- Green preparation process for preparing 5-fluorouracil
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The invention relates to a green method for preparing 5-fluorouracil, which is characterized in that the preparation method comprises the following steps: stirring 2-methoxy-5-fluorouracil serving as a raw material and a methanol solution of hydrogen chloride serving as an acidifying reagent at a certain temperature for 5-6 hours, carrying out HPLC central control, cooling to 15 DEG C after the reaction is finished, carrying out suction filtration to obtain a solid, refining to obtain a 5-fluorouracil refined product, carrying out suction filtration, concentrating mother liquor, recovering methanol, introducing hydrogen chloride into the recovered methanol, and continuously taking the recovered methanol as an acidifying reagent of the reaction; and the specific reaction is shown in the specification. The green method has the advantages that hydrochloric acid is replaced by an organic solvent, the organic solvent can be recycled after the reaction is finished, the problem that a large amount of concentrated acid wastewater is generated is solved, and the resource utilization rate is increased while environmental pollution is prevented. In addition, the reaction is centrally controlled by a liquid chromatograph in the later stage of the reaction, the reaction efficiency is improved, the obtained 5-fluorouracil is qualified in purity and stable in yield, and the method is a green chemical synthesis method with good popularization and application prospects.
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Paragraph 0012-0015
(2021/07/17)
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- The Peculiar Case of the Hyper-thermostable Pyrimidine Nucleoside Phosphorylase from Thermus thermophilus**
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The poor solubility of many nucleosides and nucleobases in aqueous solution demands harsh reaction conditions (base, heat, cosolvent) in nucleoside phosphorylase-catalyzed processes to facilitate substrate loading beyond the low millimolar range. This, in turn, requires enzymes that can withstand these conditions. Herein, we report that the pyrimidine nucleoside phosphorylase from Thermus thermophilus is active over an exceptionally broad pH (4–10), temperature (up to 100 °C) and cosolvent space (up to 80 % (v/v) nonaqueous medium), and displays tremendous stability under harsh reaction conditions with predicted total turnover numbers of more than 106 for various pyrimidine nucleosides. However, its use as a biocatalyst for preparative applications is critically limited due to its inhibition by nucleobases at low concentrations, which is unprecedented among nonspecific pyrimidine nucleoside phosphorylases.
- Kaspar, Felix,Neubauer, Peter,Kurreck, Anke
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p. 1385 - 1390
(2021/01/29)
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- General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation in Vivo
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Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.
- Sun, Tao,Lv, Tian,Wu, Jianbing,Zhu, Mingchao,Fei, Yue,Zhu, Jie,Zhang, Yihua,Huang, Zhangjian
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p. 13899 - 13912
(2020/12/02)
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- Halogenation and nitration of 1-carboxymethyl-5-methyluracil. Halophilic reaction involving acetic anhydride
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1-Carboxymethyl-5-halo-6-hydroxy-5-methyl-5,6-dihydrouracils and 1-carboxymethyl-6-hydroxy-5-methyl-5-mtro-5,6-dihydrouracils were synthesized for the first time by oxidative halogenation and nitration of 1-carboxymethyl-5-methyluracil. Dihydrouracil derivatives bearing a Br atom at position C(5) and a hydroxy group at position C(6) treated with Ac2O undergo deoxyhalogenation.
- Chernikova, I. B.,Yunusov, M. S.
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p. 2159 - 2162
(2020/12/07)
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- Thermodynamic Reaction Control of Nucleoside Phosphorolysis
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Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
- Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
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supporting information
p. 867 - 876
(2020/01/24)
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- Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation
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The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.
- Oliveira, Bruno L.,Stenton, Benjamin J.,Unnikrishnan,De Almeida, Cátia Rebelo,Conde, Jo?o,Negr?o, Magda,Schneider, Felipe S.S.,Cordeiro, Carlos,Ferreira, Miguel Godinho,Caramori, Giovanni F.,Domingos, Josiel B.,Fior, Rita,Bernardes, Gon?alo J. L.
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supporting information
p. 10869 - 10880
(2020/07/04)
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- Enhanced Tumor Selectivity of 5-Fluorouracil Using a Reactive Oxygen Species-Activated Prodrug Approach
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We report the design, synthesis, and evaluation of novel 5-fluorouracil (5FU) prodrugs 1a,1b that are efficiently activated by the high level of reactive oxygen species (ROS) in cancer cells. Prodrugs 1a,1b selectively kill cancer cells over normal cells and are well-tolerated in mice. The strategy described herein can extend application of chemotherapeutic drugs.
- Ai, Yong,Obianom, Obinna N.,Kuser, Meredith,Li, Yue,Shu, Yan,Xue, Fengtian
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supporting information
p. 127 - 131
(2019/01/04)
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- Composition of 5-fluorouracil and preparation method of composition
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The invention discloses a refining method of 5-fluorouracil. The method comprises the following steps: dissolving 5-fluorouracil into an organic solvent, preferably DMSO (dimethyl sulfoxide), and performing heating and stirring till dissolution; naturally cooling filtrate till a crystal is separated; performing filtration, washing filter cakes by using a polar solvent, and performing pumping and vacuum drying. By adopting the novel refining method, the content of impurities in the 5-fluorouracil can be reduced to 0.01% or less, the product purity is 99.98% or greater, and the refining yield isgreater than 70%. In addition, the refining method disclosed by the invention is simple in process, convenient in operation, low in production cost, high in product purity, stable in process and applicable to industrial production.
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Paragraph 0061; 0067-0070
(2019/11/12)
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- Plasmonically Coupled Nanoreactors for NIR-Light-Mediated Remote Stimulation of Catalysis in Living Cells
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Artificial nanoreactors that can facilitate catalysis in living systems on-demand with the aid of a remotely operable and biocompatible energy source are needed to leverage the chemical diversity and expediency of advanced chemical synthesis in biology and medicine. Here, we designed and synthesized plasmonically integrated nanoreactors (PINERs) with highly tunable structure and NIR-light-induced synergistic function for efficiently promoting unnatural catalytic reactions inside living cells. We devised a synthetic approach toward PINERs by investigating the crucial role of metal-tannin coordination polymer nanofilm - the pH-induced decomplexation-mediated phase-transition process - for growing arrays of Au-nanospheroid-units, constructing a plasmonic corona around the proximal and reactant-accessible silica-compartmentalized catalytic nanospace. Owing to the extensive plasmonic coupling effect, PINERs show strong and tunable optical absorption in the visible to NIR range, ultrabright plasmonic light scattering, controllable thermoplasmonic effect, and remarkable catalysis; and, upon internalization by living cells, PINERs are highly biocompatible and demonstrate dark-field microscpy-based bioimaging features. Empowered with the synergy between plasmonic and catalytic effects and reactant/product transport, facilitated by the NIR-irradiation, PINERs can perform intracellular catalytic reactions with dramatically accelerated rates and efficiently synthesize chemically activated fluorescence-probes inside living cells.
- Kumar, Amit,Kumar, Sumit,Kumari, Nitee,Lee, Seon Hee,Han, Jay,Michael, Issac J.,Cho, Yoon-Kyoung,Lee, In Su
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p. 977 - 990
(2019/01/15)
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- Tetrahydrofuran substituted uracil compound for treating liver cancer as well as pharmaceutical composition and application thereof
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The invention provides a tetrahydrofuran substituted uracil compound for treating liver cancer as well as a pharmaceutical composition and application thereof. The tetrahydrofuran substituted uracil compound has a following chemical structure shown as a formula A. The structural formula is as shown in the description. The tetrahydrofuran substituted uracil compound disclosed by the invention has high inhibitory activity, is capable of interfering synthesis of tumor cell DNA and proteins thereof in vivo so as to inhibit tumor formation and growth of the liver cancer, and can further obviously inhibit pulmonary metastasis and intrahepatic dissemination of the liver cancer.
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Paragraph 0027-0029
(2018/12/13)
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- Green method for preparing 5-fluorouracil
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The invention relates to a green method for preparing 5-fluorouracil. The green method is characterized in that 2-methoxyl-5-fluorouracil serves as a raw material, methanol solution of hydrogen chloride serves as an acidification reagent, the raw material is stirred for 5-6 hours at a certain temperature, center control is performed by HPLC (high performance liquid chromatography), the temperatureis reduced to 15 DEG C after reaction, solids obtained by suction filtration are refined to obtain high-quality 5-fluorouracil, mother liquid is concentrated after suction filtration, methyl alcoholis recycled, hydrogen chloride is led into the recycled methyl alcohol to continue serving as the acidification reagent of the reaction, and specific reaction is as shown in the specification. The green method has the advantages that an organic solvent is used for replacing hydrochloric acid and can be recycled after reaction, the problem of generation of a large quantity of concentrated acid wastewater is solved, and resource utilization rate is increased while environmental pollution is prevented. Besides, the reaction is subjected to center control by a liquid chromatograph in a later reaction period, reaction efficiency is improved, the purity of the obtained 5-fluorouracil is qualified, the yield of the 5-fluorouracil is stable, and the method is a green chemical synthesis method witha good popularization and application prospect.
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Paragraph 0005; 0011-0014
(2018/05/07)
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- Method for fluorinating pyrimidine derivative by using micro-channel reactor
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The invention discloses a method for directly fluorinating a pyrimidine derivative by using a micro-channel reactor. A uracil and/or cytosine and fluorine-containing acid and/or fluorine-containing alcohol mixture used as a raw material reacts with fluorine to prepare corresponding fluorouracil and/or fluorocytosine. The prepared fluorouracil and fluorocytosine have the advantages of high purity, low cost advantage, and safe and easily controlled fluorination process.
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Paragraph 0028-0031; 0057-0061
(2017/06/02)
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- In-Cell Dual Drug Synthesis by Cancer-Targeting Palladium Catalysts
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Transition metals have been successfully applied to catalyze non-natural chemical transformations within living cells, with the highly efficient labeling of subcellular components and the activation of prodrugs. In vivo applications, however, have been scarce, with a need for the specific cellular targeting of the active transition metals. Here, we show the design and application of cancer-targeting palladium catalysts, with their specific uptake in brain cancer (glioblastoma) cells, while maintaining their catalytic activity. In these cells, for the first time, two different anticancer agents were synthesized simultaneously intracellularly, by two totally different mechanisms (in situ synthesis and decaging), enhancing the therapeutic effect of the drugs. Tumor specificity of the catalysts together with their ability to perform simultaneous multiple bioorthogonal transformations will empower the application of in vivo transition metals for drug activation strategies.
- Clavadetscher, Jessica,Indrigo, Eugenio,Chankeshwara, Sunay V.,Lilienkampf, Annamaria,Bradley, Mark
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supporting information
p. 6864 - 6868
(2017/06/06)
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- TETRAZINE AS A TRIGGER TO RELEASE CAGED CARGO
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There is presented a kit comprising a masked active agent and a tetrazine trigger, the masked active agent comprising an active agent connected to a masking moiety comprising a monovinyl ether or an active agent enclosed within a cage moiety comprising a monovinyl ether or an allyl group, wherein the tetrazine trigger is configured to release the active agent from the masking moiety or the cage moiety. Methods of preparing the masked active agents, and uses of the kit are also presented.
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Page/Page column 48
(2017/04/11)
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- SUBSTANCE-CONTAINING VESICLE, AND PRODUCTION METHOD THEREFOR
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Provided is a monodisperse agglomerate of a substance-containing vesicle filled with a substance at a concentration higher than conventionally possible. A mixed solution, in which a target substance is included in an aqueous medium, is mixed with a monodisperse agglomerate of a crosslinked vesicle comprising a prescribed polymer which includes a first polymer, i.e. a block copolymer having uncharged hydrophilic segments and first charged segments, and a second polymer having second charged segments carrying a charge opposite to that of the first charged segments, and in which the first polymer and/or the second polymer are/is crosslinked. As a result, the crosslinked vesicle is made to contain the target substance.
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Paragraph 0387
(2016/01/25)
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- Effect of CYP2A6 genetic polymorphism on the metabolic conversion of tegafur to 5-fluorouracil and its enantioselectivity
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Tegafur (FT), a prodrug of 5-fluorouracil, is a chiral molecule, a racemate of R- and S-isomers, and CYP2A6 plays an important role in the enantioselective metabolism of FT in human liver microsomes (R-FT ? S-FT). This study examined the enantioselective metabolism of FT by microsomes prepared from Sf9 cells expressing wild-type CYP2A6 and its variants (CYP2A6*7,*8, *10, and*11) that are highly prevalent in the Asian population. We also investigated the metabolism of coumarin and nicotine, both CYP2A6 probe drugs, in these variants. Enzyme kinetic analyses showed that CYP2A6.7 (I471T) and CYP2A6.10 (I471T and R485L) had markedly lower Vmax values for both enantiomers than wild-type enzyme (CYP2A6.1) and other variant enzymes, whereas Km values were higher in most of the variant enzymes for both enantiomers than CYP2A6.1. The ratios of Vmax and Km values for R-FT to corresponding values for S-FT (R/S ratio) were similar among enzymes, indicating little difference in enantioselectivity among the wild-type and variant enzymes. Similarly, both CYP2A6.7 and CYP2A6.10 had markedly lower Vmax values for coumarin 7-hydroxylase and nicotine C-oxidase activities than CYP2A6.1 and other variant enzymes, whereas Km values were higher in most of the variant enzymes for both activities than CYP2A6.1. In conclusion, the amino acid substitutions in CYP2A6 variants generally resulted in lower affinity for substrates, while Vmax values were selectively reduced in CYP2A6.7 and CYP2A6.10. Consistent R/S ratios among CYP2A6.1 and variant enzymes indicated that the amino acid substitutions had little effect on enantioselectivity in the metabolism of FT. Copyright
- Yamamiya, Ikuo,Yoshisue, Kunihiro,Ishii, Yuji,Yamada, Hideyuki,Chiba, Masato
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p. 1485 - 1492
(2014/11/27)
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- Discovery of a bacterial 5-methylcytosine deaminase
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5-Methylcytosine is found in all domains of life, but the bacterial cytosine deaminase from Escherichia coli (CodA) will not accept 5-methylcytosine as a substrate. Since significant amounts of 5-methylcytosine are produced in both prokaryotes and eukaryotes, this compound must eventually be catabolized and the fragments recycled by enzymes that have yet to be identified. We therefore initiated a comprehensive phylogenetic screen for enzymes that may be capable of deaminating 5-methylcytosine to thymine. From a systematic analysis of sequence homologues of CodA from thousands of bacterial species, we identified putative cytosine deaminases where a "discriminating" residue in the active site, corresponding to Asp-314 in CodA from E. coli, was no longer conserved. Representative examples from Klebsiella pneumoniae (locus tag: Kpn00632), Rhodobacter sphaeroides (locus tag: Rsp0341), and Corynebacterium glutamicum (locus tag: NCgl0075) were demonstrated to efficiently deaminate 5-methylcytosine to thymine with values of kcat/Km of 1.4 × 105, 2.9 × 104, and 1.1 × 103 M-1 s-1, respectively. These three enzymes also catalyze the deamination of 5-fluorocytosine to 5-fluorouracil with values of kcat/Km of 1.2 × 105, 6.8 × 104, and 2.0 × 102 M-1 s-1, respectively. The three-dimensional structure of Kpn00632 was determined by X-ray diffraction methods with 5-methylcytosine (PDB id: 4R85), 5-fluorocytosine (PDB id: 4R88), and phosphonocytosine (PDB id: 4R7W) bound in the active site. When thymine auxotrophs of E. coli express these enzymes, they are capable of growth in media lacking thymine when supplemented with 5-methylcytosine. Expression of these enzymes in E. coli is toxic in the presence of 5-fluorocytosine, due to the efficient transformation to 5-fluorouracil.
- Hitchcock, Daniel S.,Fedorov, Alexander A.,Fedorov, Elena V.,Almo, Steven C.,Raushel, Frank M.
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p. 7426 - 7435
(2015/04/16)
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- Characterization of pyrimidine nucleoside phosphorylase of Mycoplasma hyorhinis: Implications for the clinical efficacy of nucleoside analogues
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In the present paper we demonstrate that the cytostatic and antiviral activity of pyrimidine nucleoside analogues is markedly decreased by a Mycoplasma hyorhinis infection and show that the phosphorolytic activity of the mycoplasmas is responsible for this. Since mycoplasmas are (i) an important cause of secondary infections in immunocompromised (e.g. HIV infected) patients and (ii) known to preferentially colonize tumour tissue in cancer patients, catabolic mycoplasma enzymesmay compromise efficient chemotherapy of virus infections and cancer. In the genome of M. hyorhinis, a TP (thymidine phosphorylase) gene has been annotated. This gene was cloned, expressed in Escherichia coli and kinetically characterized. Whereas the mycoplasma TP efficiently catalyses the phosphorolysis of thymidine (Km = 473 μM) and deoxyuridine (Km = 578 μM), it prefers uridine (K m =92 μM) as a substrate. Our kinetic data and sequence analysis revealed that the annotated M. hyorhinis TP belongs to the NP (nucleoside phosphorylase)-II class PyNPs (pyrimidine NPs), and is distinct from the NP-II class TP and NPI class UPs (uridine phosphorylases). M. hyorhinis PyNP also markedly differs from TP and UP in its substrate specificity towards therapeutic nucleoside analogues and susceptibility to clinically relevant drugs. Several kinetic properties of mycoplasma PyNP were explained by in silico analyses. The Authors Journal compilation
- Vande Voorde, Johan,Gago, Federico,Vrancken, Kristof,Liekens, Sandra,Balzarini, Jan
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experimental part
p. 113 - 123
(2012/10/23)
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- PHOSPHORAMIDATE DERIVATIVES OF 5 - FLUORO - 2 ' - DEOXYURIDINE FOR USE IN THE TREATMENT OF CANCER
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Phosphoramidate derivatives of 5-fluoro-2'-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside transporter proteins and/or with nucleoside kinase-deficient cells and/or with mycoplasma-infected cells and/or with cells with a raised level of thymidylate synthase.
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Page/Page column 65
(2012/09/21)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2′-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes
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A novel phosphoramidate nucleotide prodrug of the anticancer nucleoside analogue 5-fluoro-2′-deoxyuridine (5-FdUrd) was synthesized and evaluated for its cytostatic activity. Whereas 5-FdUrd substantially lost its cytostatic potential in thymidine kinase (TK)-deficient murine leukaemia L1210 and human lymphocyte CEM cell cultures, NUC-3073 markedly kept its antiproliferative activity in TK-deficient tumour cells, and thus is largely independent of intracellular TK activity to exert its cytostatic action. NUC-3073 was found to inhibit thymidylate synthase (TS) in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC-3073 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). These findings are in line with our observations that 5-FdUrd, but not NUC-3073, substantially loses its cytostatic potential in the presence of TP-expressing mycoplasmas in the tumour cell cultures. Therefore, we propose NUC-3073 as a novel 5-FdUrd phosphoramidate prodrug that (i) may circumvent potential resistance mechanisms of tumour cells (e.g. decreased TK activity) and (ii) is not degraded by catabolic enzymes such as TP which is often upregulated in tumour cells or expressed in mycoplasma-infected tumour tissue.
- Vande Voorde, Johan,Liekens, Sandra,McGuigan, Christopher,Murziani, Paola G.S.,Slusarczyk, Magdalena,Balzarini, Jan
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experimental part
p. 441 - 452
(2012/01/14)
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- Design and synthesis of a β-lactamase activated 5-fluorouracil prodrug
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An efficient synthesis of a 5-fluorouracil-cephalosporin prodrug is described for use against colorectal and other cancers in antibody and gene-directed therapies. The compound shows stability in aqueous media until specifically activated by β-lactamase (
- Phelan, Ryan M.,Ostermeier, Marc,Townsend, Craig A.
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body text
p. 1261 - 1263
(2009/08/07)
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- New [11C]phosgene based synthesis of [11C]pyrimidines for positron emission tomography
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Thymine, 5-FU, and uracil were successfully synthesized through a procedure involving a cyclocondensation of triphosgene with newly developed (α-substituted β-aminoacrylamides intermediates (1a, X= Me; 1b, X= F; 1c, X= H). The radioligands [2-11C]thymine and [2- 11C]5-fluorouracil were synthesized in high radiochemical yields in 16-17 minutes from the end of bombardment by applying the cyclocondensation method with [11C]COCl2.
- Seki, Koh-Ichi,Nishijima, Ken-Ichi,Sanoki, Kimihito,Kuge, Yuji,Takahashi, Masayuki,Akizawa, Hiromichi,Tamaki, Nagara,Wiebe, Leonard I.,Ohkura, Kazue
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experimental part
p. 1307 - 1321
(2010/10/03)
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- Phase I and phase II ocular metabolic activities and the role of metabolism in ophthalmic prodrug and codrug design and delivery
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While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic capabilities of the eye are minuscule; however, phase I and phase II metabolic activities have been detected in various ocular structures. The careful consideration of ocular tissue metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and for providing the potential for site-specific bio-activation of certain drug molecules, thus enabling significant improvements in drug efficacy and the minimization of side-effect from either local or systemic drug delivery to the eye. Knowledge of these processes is important to prodrug and codrug development and to researchers involved in the design, delivery and metabolism of ophthalmic drugs. This present article reviews the progress in ocular prodrug and codrug design and delivery in light of ocular metabolic activities.
- Al-Ghananeem, Abeer M.,Crooks, Peter A.
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p. 373 - 388
(2007/10/03)
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- USE OF MESENCHYMAL STEM CELLS GENETICALLY MODIFIED TO EXPRESS A SUICIDE GENE FOR TREATING A CANCER
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Mesenchymal stem cells expressing a suicide gene show excellent and highly selective anticancer effects against cancer tissues through the selective conversion of a prodrug of an anticancer agent to the anticancer agent at around the cancer. Also disclosed herein are a pharmaceutical composition for treating a cancer comprising the mesenchymal stem cell; a kit for treating a cancer comprising an expression vector comprising the suicide gene, the mesenchymal stem cell and the prodrug; and a method for treating a cancer patient, which comprises successively administering the mesenchymal stem cell and the prodrug to the patient.
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Page/Page column 16; 17
(2008/06/13)
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- Compositions and methods for coating medical implants
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Medical implants are provided which release an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, and/or platinum complex, thereby inhibiting or reducing the incidence of infection associated with the implant.
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- Agents for corneal or intrastromal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing dissolution of corneal proteoglycans and organized healing of corneal stroma, softening of the cornea for non-surgical refractive correction of eyesight, removing corneal haze and opacification, inhibiting fibroblasts and preventing corneal fibrosis and scar formation, treating pterigiums and treating corneal neovascularization as well as iris neovascularization. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) antimetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate, isopropyl alcohol, ethanol, polyethylene glycol, polypropylene glycol or other compound capable of causing nonenzymatic dissolution of the corneal protoeglycans or f) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Synthesis and cytotoxicity of 5-fluorouracil/diazeniumdiolate conjugates
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5-Fluorouracil/diazeniumdiolate conjugates were first synthesized, and showed greater cytotoxicities than 5-fluorouracil for DU 145 human prostate and HeLa cancer cells.
- Cai, Tingwei Bill,Tang, Xiaoping,Nagorski, Janet,Brauschweiger, Paul G.,Wang, Peng George
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p. 4971 - 4975
(2007/10/03)
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- Method and compositions for the treatment of pruritus
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A composition for treating pruritus, comprising a compound selected from the group consisting of opioid receptor antagonists, opioid receptor agonists/antagonists, and pharmaceutically acceptable salts thereof, and a compound useful in treating the cause of the pruritus. This invention also relates to a method of treating pruritus using such compositions, and a method for preparing these compositions.
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- Agents for intravitreal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing posterior vitreous disconnection or disinsertion. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) a non-steroidal anti-inflamatory agents, d) antmetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, thymidine, thimitadine, uradine, uracil, cystine), uric acid, calcium acetal salicylate, ammonium sulfate or other compound capable of causing non-enzymatic dissolution of the hyaloid membrane or e) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Kinetic model for 5-fluorouridine degradation: Catalytic effect of 5-fluorouracil
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The effects of 5-fluorouridine (5-FUR, CAS 316-46-1) degradation products, 5-fluorouracil (5-FU, CAS 51-21-8) and D-ribose (CAS 50-69-1), on its degradation rate was investigated following a 23 factorial design. The experimental data fitted to the proposed mathematical model which includes two parallel degradation mechanisms: the first one, a second order bimolecular reaction involving both 5-FUR and 5-FU, and the second, a first order one. Experimental data obtained show a high variability. Both graphic and statistical analysis of the experiments for which a full kinetic model was applied manifested that the degradation mechanism included an autocatalytic route and confirmed the role of the 5-FU on the hydrolysis of 5-FUR.
- Dorta,Munguia,Llabres
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p. 858 - 861
(2007/10/03)
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- Synthesis and hydrolytic stability of the α and β anomers of 4′-thio-2′-deoxyuridine and their 5-substituted analogs. Competition between the acid-catalysed depyrimidination and isomerisation to a 5-thiopyranoside nucleoside
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The α and β anomers of 4′-thio-2′-deoxyuridine were readily synthesised as an anomeric mixture using adapted methodology and separated chromatographically as their 3′,5′-di-O-benzyl-N3-benzoyl derivatives. The 5-fluoro analogs were prepared in a similar manner, but the anomers could be separated simply as their 3,5-di-O-benzyl derivatives. The kinetics of acid-catalysed hydrolysis for the four compounds and their 5-alkylated analogs are reported. Under these conditions, cleavage of the N-glycosidic bond competes with the reversible isomerisation between the furano (4′-thio) and pyrano (5′-thio) ring systems. This was confirmed by isolation and NMR characterisation of the α and β pyranose intermediates of the parent compounds.
- Otter, Graham P.,Elzagheid, Mohamed I.,Jones, Garry D.,MacCulloch, Alasdair C.,Walker, Richard T.,Oivanen, Mikko,Klika, Karel D.
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p. 2343 - 2349
(2007/10/03)
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- Silyl modification of biologically active compounds. 5. Hydrolytic stability and biological activity of the trialkylsilyl derivatives of some heterocyclic bases
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The kinetics of the desilylation of the triorganosilyl derivatives of some biologically active heterocyclic bases and uridine were investigated by 1H NMR spectroscopy. A correlation was established between the relative rates of desilylation and the steric environment of the silicon atom. In trials on locomotor activity and muscular tone, the effect on memory processes, and the Porsolt test it was found that tris(tert-butylmethylsilyl)barbituric acid has higher sedative activity than barbituric acid. In contrast to uridine, 5′-O-tert-butyldimethylsilyluridine exhibits antitumor activity, suppressing the development of fibrosarcoma in human lungs (HT-1080) and fibroblasts in mice. 1999 Kluwer Academic/Plenum Publishers.
- Lukevits,Segal,Birgele,Zablotskaya
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p. 1076 - 1080
(2007/10/03)
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- Stability indicating high performance liquid chromatography methods for 5-fluorouridine in aqueous solution
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Two methods of reversed-phase high performance liquid chromatography (RP-HPLC) were used to detect and quantify the degradation of 5-fluorouridine (CAS 316-46-1, 5-FUR) in aqueous solution. The 1H-NMR technique was used for identifying the degradation products. Several assays were performed from different aqueous solutions of 5-FUR. The best results (optimal resolution, reproducibility and rapidity) were achieved by using Resolve C-18 as stationary phase and a mix (96:4) of 50 mmol/l ammonium dihydrogen phosphate (adjusted to pH 3.5 with phosphoric acid) and acetonitrile as mobile phase. Despite the 5-FUR hydrolysis to 5-fluorouracil (5-FU) and D-ribose under moderate conditions in unlikely, due to high stability of the nucleoside, these were the identified degradation products in assays carried out.
- Dorta, Maria J.,Munguia, Obdulia,Farina, Jose B.,Martin, Victor S.,Llabres, Matias
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p. 1388 - 1392
(2007/10/03)
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- Synthesis and reactivity of 5-fluorouracil/cytarabine mutual prodrugs
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Two mutual prodrugs, in which two different anti-cancer drugs are attached to the same molecule via labile linkages, are synthesized and examined kinetically. One of the mutual prodrugs loses a drug component under physiological conditions within an hour, but the other mutual prodrug (having a longer spacer between the two drugs) is stable to chemical degradation even at hither pH values. Thus, enzymatic hydrolysis alone will release the two anti-cancer drugs. The potential value of anti-cancer mutual prodrugs is discussed.
- Menger, Fredric M.,Rourk, Michael J.
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p. 9083 - 9088
(2007/10/03)
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- Photodegradation of antimycotic drugs. 4. Communication: Photodegradation of flucytosine and griseofulvin
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The antimycotic drug substances flucytosine and griseofulvin are degraded under the influence of light. A liquid chromatography-mass spectrometry system helped us to elucidate some of the photodegradation pathways. 5-Fluorouracil is one of the photodegradation products of flucytosine in aqueous solution. The photodegradation of griseofulvin in solutions is mainly influenced by the solvent. The photodegradation product deschlorgriseofulvin could be detected in aqueous solution as well as in ethanolic and methanolic solution. Two photodegradation products found in ethanolic solution could, however, not be detected in methanolic or aqueous solution. Storage instructions of the pharmocopoeias are quite surprising. The US and the German pharmacopoeia recommend light protected storage for flucytosine but not for griseofulvin although griseofulvin is photodegraded more rapidly than flucytosine.
- Thoma,Kuebler,Reimann
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p. 455 - 463
(2007/10/03)
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