- Activation of antibacterial prodrugs by peptide deformylase
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5'-Dipeptidyl derivatives of 5-fluorodeoxyuridine (FdU) (1a-d) were synthesized. These compounds are biologically inactive but can be activated by peptide deformylase, which removes the N-terminal formyl group of the dipeptide, to release the active drug FdU via an intramolecular cyclization reaction. Because the deformylase is ubiquitous among bacteria but absent in mammalian cells, 1a-d provide a novel class of potential antibacterial agents. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Wei, Yaoming,Pei, Dehua
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- Floxuridine Oligomers Activated under Hypoxic Environment
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Floxuridine oligomers are anticancer oligonucleotide drugs composed of a number of floxuridine residues. They show enhanced cytotoxicity per floxuridine monomer because the nuclease degradation of floxuridine oligomers directly releases highly active floxuridine monophosphate in cells. However, their clinical use is limited by the low selectivity against cancer cells. To address this limitation, we herein report floxuridine oligomer prodrugs that are active under hypoxia conditions, which is one of the distinguishing features of the microenvironment of all solid tumors. We designed and synthesized two types of floxuridine oligomer prodrugs that possess hypoxia-responsive moieties on nucleobases. The floxuridine oligomer prodrugs showed lower cytotoxicity under normoxia conditions (O2 = 20%), while the parent floxuridine oligomer showed similar anticancer effects under hypoxia conditions (O2 = 1%). The floxuridine oligomer prodrug enabled tumor growth suppression in live mice. This would be the first example demonstrating the conditional control of the medicinal efficacy of oligomerized nucleoside anticancer drugs.
- Morihiro, Kunihiko,Ishinabe, Takuro,Takatsu, Masako,Osumi, Hiraki,Osawa, Tsuyoshi,Okamoto, Akimitsu
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- Biotransformation of halogenated 2′-deoxyribosides by immobilized lactic acid bacteria
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An efficient and green bioprocess is herein reported to obtain halogenated nucleosides by transglycosylation using immobilized lactic acid bacteria (LAB). Lactobacillus animalis ATCC 35046 showed a yield of 95% at 0.5 h to synthesize 5-fluorouracil-2′-deoxyriboside (floxuridine). Calcium alginate was the best matrix for whole-cell immobilization by entrapment. Its productivity was 87 mg/L h in a continuous bioprocess. When adsorption techniques were evaluated, DEAE-Sepharose was the support which showed higher microbial load, its productivity being 53 mg/L h. Additionally, this microorganism was able to produce 5-bromouracil-2′-deoxyriboside, 6-chloropurine-2′- deoxyriboside and 6-bromopurine-2′-deoxyriboside.
- Britos, Claudia N.,Cappa, Valeria A.,Rivero, Cintia W.,Sambeth, Jorge E.,Lozano, Mario E.,Trelles, Jorge A.
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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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- Bio-catalytic synthesis of unnatural nucleosides possessing a large functional group such as a fluorescent molecule by purine nucleoside phosphorylase
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Unnatural nucleosides are attracting interest as potential diagnostic tools, medicines, and functional molecules. However, it is difficult to couple unnatural nucleobases to the 1′-position of ribose in high yield and with β-regioselectivity. Purine nucleoside phosphorylase (PNP, EC2.4.2.1) is a metabolic enzyme that catalyses the conversion of inosine to ribose-1α-phosphate and free hypoxanthine in phosphate buffer with 100% α-selectivity. We explored whether PNP can be used to synthesize unnatural nucleosides. PNP catalysed the reaction of thymidine as a ribose donor with purine to produce 2′-deoxynebularine (3, β form) in high conversion (80%). It also catalysed the phosphorolysis of thymidine and introduced a pyrimidine base with a halogen atom substituted at the 5-position into the 1′-position of ribose in moderate yield (52-73%), suggesting that it exhibits loose selectivity. For a bulky purine substrate [e.g., 6-(N,N-di-propylamino)], the yield was lower, but addition of a polar solvent such as dimethyl sulfoxide (DMSO) increased the yield to 74%. PNP also catalysed the reaction between thymidine and uracil possessing a large functional fluorescent group, 5-(coumarin-7-oxyhex-5-yn) uracil (C4U). Conversion to 2′-deoxy-[5-(coumarin-7-oxyhex-5-yn)] uridine (dRC4U) was drastically enhanced by DMSO addition. Docking simulations between dRC4U and E. coli PNP (PDB 3UT6) showed the uracil moiety in the active-site pocket of PNP with the fluorescent moiety at the entrance of the pocket. Thus, the bulky fluorescent moiety has little influence on the coupling reaction. In summary, we have developed an efficient method for producing unnatural nucleosides, including purine derivatives and modified uracil, using PNP.
- Hatano, Akihiko,Wakana, Hiroyuki,Terado, Nanae,Kojima, Aoi,Nishioka, Chisato,Iizuka, Yu,Imaizumi, Takuya,Uehara, Sanae
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p. 5122 - 5129
(2019/10/05)
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- FLOXURIDINE SYNTHESIS
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The present invention relates to a process for the preparation of floxuridine, said process comprising reacting a compound of Formula la with a compound of Formula lla in the presence of an acid Al to provide a compound of Formula Ilia in substantially diastereomerically pure form. Floxuridine may be useful as an anti-cancer drug. Floxuridine may also be useful in the preparation of other anti-cancer drugs, e.g. NUC-3373.
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Page/Page column 33-34
(2019/04/11)
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- Use of Nucleoside Phosphorylases for the Preparation of Purine and Pyrimidine 2′-Deoxynucleosides
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Enzymatic transglycosylation – the transfer of the carbohydrate moiety from one heterocyclic base to another – is being actively developed and applied for the synthesis of practically important nucleosides. This reaction is catalyzed by nucleoside phosphorylases (NPs), which are responsible for reversible phosphorolysis of nucleosides to yield the corresponding heterocyclic bases and monosaccharide 1-phosphates. We found that 7-methyl-2′-deoxyguanosine (7-Me-dGuo) is an efficient and novel donor of the 2-deoxyribose moiety in the enzymatic transglycosylation for the synthesis of purine and pyrimidine 2′-deoxyribonucleosides in excellent yields. Unlike 7-methylguanosine, its 2′-deoxy derivative is dramatically less stable. Fortunately, we have found that 7-methyl-2′-deoxyguanosine hydroiodide may be stored for 24 h in Tris-HCl buffer (pH 7.5) at room temperature without significant decomposition. In order to optimize the reagent ratio, a series of analytical transglycosylation reactions were conducted at ambient temperature. According to HPLC analysis of the transglycosylation reactions, the product 5-ethyl-2′-deoxyuridine (5-Et-dUrd) was obtained in high yield (84–93%) by using a small excess (1.5 and 2.0 equiv.) of 7-Me-dGuo over 5-ethyluracil (5-Et-Ura) and 0.5 equiv. of inorganic phosphate. Thymidine is a less effective precursor of α-d-2-deoxyribofuranose 1-phosphate (dRib-1p) compared to 7-Me-dGuo. We synthesized 2′-deoxyuridine, 5-Et-dUrd, 2′-deoxyadenosine and 2′-deoxyinosine on a semi-preparative scale using the optimized reagent ratio (1.5:1:0.5) in high yields. Unlike other transglycosylation reactions, the synthesis of 2-chloro-2′-deoxyadenosine was performed in a heterogeneous medium because of the poor solubility of the initial 2-chloro-6-aminopurine. Nevertheless, this nucleoside was prepared in good yield. The developed enzymatic procedure for the preparation of 2′-deoxynucleosides may compete with the known chemical approaches. (Figure presented.).
- Drenichev, Mikhail S.,Alexeev, Cyril S.,Kurochkin, Nikolay N.,Mikhailov, Sergey N.
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p. 305 - 312
(2018/01/15)
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- High purity 5 - fluoro - deoxy uracil nucleoside preparation method
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The invention discloses a preparation method of high-purity 5-fluro-deoxyuridine. The preparation method comprises the following steps: (A) mixing a 5-fluro-deoxyuridine derivative as shown in a structural formula B and a reagent capable of removing hydroxyl protecting groups, and reacting at the temperature of 5-40 DEG C, thereby obtaining a reaction system A; (B) dissolving the reaction system A in an organic solvent, and crystallizing at the temperature of 0-15 DEG C, thereby obtaining the 5-fluro-deoxyuridine as shown in a structural formula A. The reagent for removing the hydroxyl protecting groups is selected from ammonia water and methanol amine, an aqueous solution of sodium hydroxide and potassium hydroxide, glacial acetic acid, trifluoroacetic acid or tetrabutylammonium fluoride.
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Paragraph 0154; 0155; 0156; 0157; 0158; 0159
(2017/08/25)
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- THERMOSTABLE BIOCATALYST COMBINATION FOR NUCLEOSIDE SYNTHESIS
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The present invention relates to a transglycosylation method for the preparation of natural and synthetic nucleosides using a uridine phosphorylase (PyNPase, E.C. 2.4.2.3), a purine nucleoside phosphorylase (PNPase, E.C. 2.4.2.1), or a combination thereof. These biocatalysts may be used as such, or by means of host cells transformed with vectors comprising recombinant DNA gene derived from hyperthermophilic archaea and encoding for the PyNPase and PNPase enzymes.
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Paragraph 0090-0091
(2016/08/17)
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- Biotransformation of halogenated nucleosides by immobilized Lactobacillus animalis 2′-N-deoxyribosyltransferase
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An immobilized biocatalyst with 2′-N-deoxyribosyltransferase (NDT) activity, Lactobacillus animalis NDT (LaNDT), was developed from cell free extracts. LaNDT was purified, characterized and then immobilized by ionic interaction. Different process parameters were optimized, resulting in an active derivative (2.6 U/g) able to obtain 1.75 mg/g of 5-fluorouracil-2′-deoxyriboside, an antimetabolite known as floxuridine, used in gastrointestinal cancer treatment. Furthermore, immobilized LaNDT was satisfactorily used to obtain at short reaction times other halogenated pyrimidine and purine 2′-deoxynucleosides such as 6-chloropurine-2′-deoxyriboside (4.9 U/g), 6-bromopurine-2′-deoxyriboside (4.3 U/g), 6-chloro-2-fluoropurine-2′-deoxyriboside (5.4 U/g), 5-bromo-2′-deoxyuridine (2.8 U/g) and 5-chloro-2′-deoxyuridine (1.8 U/g) compounds of pharmaceutical interest in antiviral or antitumor treatments. Besides, increasing the biocatalyst amount 8 times per volume unit allowed obtaining a 5-fold improvement in floxuridine biotransformation. The developed biocatalyst proved to be effective for the biosynthesis of a wide spectrum of nucleoside analogues by employing an economical, simple and environmentally friendly methodology.
- Britos, Claudia N.,Lapponi, María José,Cappa, Valeria A.,Rivero, Cintia W.,Trelles, Jorge A.
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- BIOORTHOGONAL METHODS AND COMPOUNDS
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The invention provides a new bioorthogonal deprotection method for preparing heterocyclic compounds by bond cleavage using palladium. The methods have general application in the field of biological synthetic chemistry. Compounds, such as prodrugs, which are useful in such methods are also provided.
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- A comparison between immobilized pyrimidine nucleoside phosphorylase from Bacillus subtilis and thymidine phosphorylase from Escherichia coli in the synthesis of 5-substituted pyrimidine 2′-deoxyribonucleosides
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Pyrimidine nucleoside phosphorylase from Bacillus subtilis (BsPyNP, E.C. 2.4.2.3) and thymidine phosphorylase from Escherichia coli (EcTP, E.C. 2.4.2.4) were used, as immobilized enzymes, in the synthesis of 5-halogenated pyrimidine 2′-deoxyribonucleosides (14-18) by transglycosylation in fully aqueous medium. From the comparative study of the two biocatalysts, no remarkable differences emerged about their substrate specificity, bioconversion yield, stability in organic cosolvents (DMF and MeCN). Moreover, both biocatalysts could be recycled for at least 5 times with no loss of the productivity. Both enzymes do not accept arabinonucleosides and 2′,3′- dideoxynucleosides as substrates, whereas they catalyze bioconversions involving 5′-deoxyribonucleosides and 5-halogenated uracils. The synthesis of compounds 14-18 proceeded at a similar conversion (33-68% for BsPyNP and 25-62% for EcTP, respectively). Immobilization was found to exert, for both the biocatalysts, a dramatic enhancement of stability upon incubation in MeCN. Optimization of 5-fluoro-2′-deoxyuridine (14) synthesis (pH 7.5, 10 mM phosphate buffer, nucleoside/nucleobase 3:1 molar ratio) and subsequent scale-up afforded the target compound in 73% (EcTP) or 76% (BsPyNP) conversion (about 9 g/L).
- Serra, Immacolata,Bavaro, Teodora,Cecchini, Davide A.,Daly, Simona,Albertini, Alessandra M.,Terreni, Marco,Ubiali, Daniela
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- One-pot approach to functional nucleosides possessing a fluorescent group using nucleobase-exchange reaction by thymidine phosphorylase
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Herein, we describe β-selective coupling between a modified uracil and a deoxyribose to produce functionalized nucleosides catalyzed by thymidine phosphorylase derived from Escherichia coli. This enzyme mediates nucleobase-exchange reactions to convert unnatural nucleosides possessing a large functional group such as a fluorescent molecule, coumarin or pyrene, linked via an alkyl chain at the C5 position of uracil. 5-(Coumarin-7-oxyhex-5- yn)uracil (C4U) displayed 57.2% conversion at 40% DMSO concentration in 1.0 mM phosphate buffer pH 6.8 to transfer thymidine to an unnatural nucleoside with C4U as the base. In the case of using 5-(pyren-1-methyloxyhex-5-yn)uracil (P4U) as the substrate, TP also could catalyse the reaction to generate a product with a very large functional group at 50% DMSO concentration (21.6% conversion). We carried out docking simulations using MF myPrest for the modified uracil bound to the active site of TP. The uracil moiety of the substrate binds to the active site of TP, with the fluorescent moiety linked to the C5 position of the nucleobase located outside the surface of the enzyme. As a consequence, the bulky fluorescent moiety binding to uracil has little influence on the coupling reaction.
- Hatano, Akihiko,Kurosu, Masayuki,Yonaha, Susumu,Okada, Munehiro,Uehara, Sanae
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p. 6900 - 6905
(2013/10/08)
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- A dramatic concentration effect on the stereoselectivity of N-glycosylation for the synthesis of 2′-deoxy-β-ribonucleosides
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A dramatic concentration effect on the stereoselectivity of N-glycosylation, which is attributable to a low-concentration-facilitated remote-participation, has been disclosed, leading to convenient synthesis of the 2′-deoxy-β-ribonucleosides of biological significance. The Royal Society of Chemistry 2012.
- Yang, Fei,Zhu, Yugen,Yu, Biao
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supporting information; experimental part
p. 7097 - 7099
(2012/08/07)
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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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- 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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- 3-Aminoxypropionate-based linker system for cyclization activation in prodrug design
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A novel linker system based on 3-aminoxypropionate was designed and evaluated for drug release using proteolysis as an activation trigger followed by intramolecular cyclization. The hydroxylamine moiety present in the linker system enabled faster release of the parent drug from the linker-drug conjugate at lower pH as compared to an aliphatic amine moiety. Introduction of two methyl groups strategically at the α position to the carboxylate in the linker further improved the rate of cyclization by nearly 2-fold. The 3-aminoxypropionate linker was successfully applied to a model prodrug for protease activation using α-chymotrypsin as the activating enzyme; the activation of the model prodrug bearing the 3-aminoxypropionate linker was 136 times faster than the corresponding model prodrug bearing an amine linker.
- Ge, Yiyu,Wu, Xinghua,Zhang, Dazhi,Hu, Longqin
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scheme or table
p. 941 - 944
(2009/08/15)
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- Chemoenzymatic preparation of nucleosides from furanoses
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Chemoenzymatic preparation of ribose, deoxyribose and arabinose 5-phosphates was accomplished. These compounds were tested as starting materials in the enzymatic preparation of natural and modified purine and pyrimidine nucleosides, using an overexpressed Escherichia coli phosphopentomutase.
- Taverna-Porro, Marisa,Bouvier, Leon A.,Pereira, Claudio A.,Montserrat, Javier M.,Iribarren, Adolfo M.
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p. 2642 - 2645
(2008/09/19)
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- Importance of 3′-hydroxyl group of the nucleosides for the reactivity of thymidine phosphorylase from Escherichia coli
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Thymidine phosphorylase in phosphate buffer catalyzed the conversion of thymidine to unnatural nucleosides. The 3′-OH, but not the 5′-OH of ribosyl moiety is necessary to be recognized as a substrate. Thus 3′-deoxythymidine could not convert to 5-fluorouracil-2′,3′- dideoxyribose. However, 5′-deoxythymidine was converted to 5-fluorouracil-2′,5′-dideoxyribose. Copyright
- Hatano, Akihiko,Harano, Aiko,Kirihara, Masayuki
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p. 232 - 233
(2007/10/03)
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- A new class of 5-fluoro-2′-deoxyuridine prodrugs conjugated with a tumor-homing cyclic peptide CNGRC by ester linkers: Synthesis, reactivity, and tumor-cell-selective cytotoxicity
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Purpose. Tumor-targeting prodrugs of 5-fluoro-2′-deoxyuridine (5-FdUrd), which are chemical conjugations of 5-FdUrd with a tumor-homing cyclic peptide CNGRC by succinate and glutarate linkers, were synthesized to investigate the structural effects of linkers on the hydrolytic release of 5-FdUrd and the tumor-cell-selective cytotoxicity. Methods. A solid phase synthesis method was used to produce 5-FdUrd prodrugs. The kinetics and efficiency of hydrolytic 5-FdUrd release from the prodrugs were investigated in phosphate buffer (PB), fetal bovine serum (FBS), HT-1080 cell lysate, MDA-MB-231 cell lysate, and MEM containing 10% FBS. The tumor-cell-selective cytotoxicity of prodrugs was evaluated by an MTT method. Results. Two tumor-targeting prodrugs CNF1 and CNF2 bearing 5-FdUrd conjugated with a common cyclic peptide CNGRC by succinate and glutarate linkers, respectively, and their control compounds CN1 and CN2 without 5-FdUrd moiety were synthesized and identified. CNF1 underwent hydrolysis to release 5-FdUrd more rapidly and efficiently than CNF2. Both prodrugs were of lower cytotoxicity compared to 5-FdUrd, showing more selective cytotoxicity toward APN/CD13 positive cells (HT-1080) than toward APN/CD13 negative cells (HT-29, MDA-MB-231). Conclusions. A new class of tumor-targeting 5-FdUrd prodrugs CNF1 and CNF2 were successfully synthesized. These prodrugs targeted a tumor marker APN/CD13 to cause tumor-cell-selective cyctotoxicity due to 5-FdUrd release, the rate of which could be controlled by the structure of ester linker.
- Zhang, Zhouen,Hatta, Hiroshi,Tanabe, Kazuhito,Nishimoto, Sei-Ichi
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p. 381 - 389
(2007/10/03)
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- Anti-HCV nucleoside derivatives
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The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
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- TRANSDERMAL DEVICE CONTAINING POLYVINYLPYRROLIDONE AS SOLUBILITY ENHANCER
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A blend of at least three polymers, including a soluble polyvinylpyrrolidone, in combination with a drug provides a pressure-sensitive adhesive composition for a transdermal drug delivery system in which the drug is delivered from the pressure-sensitive adhesive composition and through dermis when the pressure-sensitive adhesive composition is in contact with human skin. Soluble polyvinylpyrrolidone increases the solubility of drug without negatively affecting the adhesivity of the composition or the rate of drug delivery from the pressure-sensitive adhesive composition
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- Lipid esters of nucleoside monophosphates and their use as immunosuppressive drugs
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The present invention is directed to new nucleoside monophosphate derivatives of lipid ester residues of general formula (I) wherein R1 represents an optionally substituted alkyl chain having 1-20 carbon atoms; R2 represents hydrogen, an optionally substituted alkyl chain having 1-20 carbon atoms; R3, R4 and R5 represent hydrogen, hydroxy, azido, amino, cyano, or halogen; X represents a valence dash, oxygen, sulfur, a sulfinyl or sulfonyl group; Y represents a valence dash, an oxygen or sulfur atom; B represents a purine and/or pyrimidine base; with the proviso that at least one of the residues R3 or R5 is hydrogen; to their tautomers and their physiologically acceptable salts of inorganic and organic acids and/or bases, as well as to processes for their preparation, and to drugs containing said compounds.
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- A photoactivated prodrug
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A photolabile derivative (1) of the anticancer drug, 5- fluorodeoxyuridine (2), was designed and synthesized as a model prodrag. Photolysis of 1 with long-wavelength UV light rapidly released 2 in solution. While compound 1 alone is nontoxic to cells, the presence of both 1 and UV irradiation (λ = 350 nm) resulted in potent inhibition of cell growth.
- Wei, Yaoming,Yan, Yinfa,Pei, Dehua,Gong, Bing
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p. 2419 - 2422
(2007/10/03)
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- Antiviral agents
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Nucleoside compounds of the formula STR1 wherein: B is a purine or a pyrimidine; X and X' are H, OH or F, provided that at least one is H; Y and Y' are H, OH, OCH3 or F, provided that at least one is H; Y' and Z together form a cyclic phosphate ester, provided that Y is H; or Z is STR2 where n is zero, one, two or three; and Z' is N3 or OCH3 ; provided that when X' and Y' are OH and Z' is N3, B is not cytosine, and when X' and Y' are OH and Z' is OCH3, B is not uracil, adenine or cytosine; and the pharmaceutically acceptable esters, ethers and salts thereof, have been found to have potent antiviral activity with a high therapeutic ratio.
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- SYNTHESIS OF 2-DEOXY-β-D-RIBONUCLEOSIDES AND2,3-DIDEOXY.β-D-PENTOFURANOSIDES ON IMMOBILIZED BACTERIAL CELLS
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Alginate gel-entrapped cells of auxotrophic thymine-dependent strain of E. coli catalyze the transfer of 2-deoxy-D-ribofuranosyl moiety of 2'-deoxyuridine to purine and pyrimidine bases as well as their aza and deaza analogs.All experiments invariably gave β-anomers; in most cases, the reaction was regiospecific, affording N9-isomers in the purine and N1-isomers in the pyrimidine series.Also a 2,3-dideoxynucleoside can serve as donor of the glycosyl moiety.The acceptor activity of purine bases depends only little on substitution, the only condition being the presence of N7-nitrogen atom.On the other hand, in the pyrimidine series the activity is limited to only a narrow choice of mostly short 5-alkyl and 5-halogeno uracil derivatives.Heterocyclic bases containing amino groups are deaminated; this can be avoided by conversion of the base to the corresponding N-dimethylaminomethylene derivative which is then ammonolyzed.The method was verified by isolation of 9-(2-deoxy-β-D-ribofuranosyl) derivatives of adenine, guanine, 2-chloroadenine, 6-methylpurine, 8-azaadenine, 8-azaguanine, 1-deazaadenine, 3-deazaadenine, 1-(2-deoxy-β-D-ribofuranosyl) derivatives of 5-ethyluracil, 5-fluorouracil, and 9-(2,3-deoxy-β-D-pentofuranosyl)hypoxanthine, 9-(2,3-deoxy-β-D-pentofuranosyl)-6-methylpurine, and other nucleosides.
- Votruba, Ivan,Holy, Antonin,Dvorakova, Hana,Guenter, Jaroslav,Hockova, Dana,et al.
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p. 2303 - 2330
(2007/10/02)
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- Synthesis and γ-radiolysis of 2'-deoxy-5-fluorouridine and 5-fluorouridine derivatives
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Seventeen compounds having a variety of substituents at the 3- and 5'-positions of 2'-deoxy-5-fluorouridine (5-FUdR) and 5-fluorouridine (5-FUR) were synthesizedd, and their γ-radiolysis in aqueous solutions were studied. The compounds having thioureido (RNHCSNH, R = H, PhCH2, acyl) and thiocarbonylamino (XCSNH, X = PhCH2S, PhO) groups at the 3-position of 5-FUdR were efficiently cleaved to give 5-FUdR with high G values upon γ-irradiation of their aqueous solutions. The active species for these cleavage reactions were hydrated electron (e-(aq)), H. and HO.. However, the compounds having a dimethylsulfoxyimino group at 3-position of 5-FUdR and 5-FUR afforded 5-FUdR and 5-FUR only under the radiolysis conditions where e-(aq) becomes a principal active species. The compound having a 2-benzoylthiazoylthiocarbonylamino group at the 3-position of 5-FUdR showed the highest reactivity toward HO.. The mechanisms of these γ-radiolysis reactions are discussed. The examination of anticellular activities of γ-irradiated compounds having a thiocarbonylamino group at the 3-position of 5-FUdR toward murine Sarcoma 180 cells revealed that these compounds may be utilized as a candidate for a radiation-induced drug (RID).
- Kuroda,Hisamura,Matsukuma,Nishikawa,Morimoto,Ashizawa,Nakamizo,Otsuji
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p. 1133 - 1142
(2007/10/02)
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- γ-Radiolysis of 2'-deoxy-5-fluorouridine derivatives with sulfur-containing substituents
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2'-Deoxy-5-fluorouridine (5-FUdR) derivatives having various types of sulfur-containing substituents at the 5'-O-position were synthesized and their γ-radiolyses were studied in aqueous solutions. The γ-radiolysis of compounds having 1,3-dithiol-2-yl and 1,3-dithian-2-yl substituents at the 5'-O-position efficiently gave 5-FUdR, specifically via the attack of hydroxyl radical. On the other hand, the γ-radiolysis of a compound having a sulfonylmethyl substituent at the 5'-O-position gave less efficiently 5-FUdR, specifically via the attack of the hydrated electron. The mechanistic features of these reactions are discussed.
- Kuroda,Hisamura,Nakamizo,Otsuji
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p. 1143 - 1147
(2007/10/02)
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- 2'-deoxy-5-fluorouridine derivatives
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Disclosed is a 2'-deoxy-5-fluorouridine derivative of the formula STR1 wherein one of R1 and R2 is a benzyl group which may optionally have substituent selected from the group consisting of C1 -C6 alkyl group, C1 -C6 alkoxy group, C1 -C3 halogenated alkyl group, halogen atom, hydroxyl group and nitro group on the phenyl ring, and the other constitutes an amino acid residue, or a salt thereof. The compounds are useful for treating cancer.
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- Method of treating nausea and vomiting with certain substituted-phenylalkylamino (and aminoacid) derivatives and other serotonin depleting agents
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A method for the treatment of emesis in a mammal, which method comprises administering to said mammal an emesis inhibiting amount of a compound which depletes serotonin in the brain of mammals; among which are compounds having the formula: STR1 wherein, R is selected from hydrogen, loweralkyl, trifluoromethyl, carboxyl, or loweralkoxycarbonyl; R1 and R2 are hydrogen or loweralkyl; Z is trifluoromethyl or halogen; the optical isomers and pharmaceutically acceptable salts thereof; two of the preferred compounds of the invention are fenfluramine and norfenfluramine.
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- REGIOSELECTIVE DEPROTECTION OF 3',5'-O-ACYLATED PYRIMIDINE NUCLEOSIDES BY LIPASE AND ESTERASE
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A lipase was found to catalyze the regioselective hydrolysis at the secondary hydroxyl group of 2'-deoxy 3',5'-di O-hexanoyl pyrimidine nuclosides, whereas a protease catalyzes that at the primary hydroxyl group.
- Uemura, Atsuhiko,Nozaki, Kenji,Yamashita, Jun-ichi,Yasumoto, Mitsugi
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p. 3819 - 3820
(2007/10/02)
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- Reaction of Acetyl Hypofluorite with Pyrimidines. Part 3. Synthesis, Stereochemistry, and Properties of 5-Fluoro-5,6-dihydropyrimidine Nucleosides
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The reaction of acetyl hypofluorite (AcOF) with unprotected uracil and cytosine nucleosides in acetic acid or water has been studied using (18)F as a tracer.For the nucleosides in general two cis-diastereoisomers of both the 6-acetoxy-5-fluoro and 5-fluoro-6-hydroxy adducts were obtained, (1)H n.m.r. analysis of which showed that they all possessed the anti-conformation.The 6-acetoxy-5-fluoroadducts in the uracil nucleosides showed a remarkable stability and appeared to be interesting versatile compounds.They could be converted into their hitherto unknown corresponding 5-fluoro-6-hydroxy-O6,5'-anhydrocyclouracil nucleosides.For the cytosine nucleosides the 6-acetoxy-5-fluoro adducts were not observed, while the other cytosine adducts were found to rapidly deaminate at C-4 in water yielding the corresponding uracil analogues.Interestingly, even within a pair of diastereoisomers different deamination rates were observed.
- Visser, Gerard W. M.,Herder, Renella E.,Noordhuis, Paul,Zwaagstra, Oene,Herscheid, Jacobus D. M.,Kanter, Frans J. J. de
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p. 2547 - 2554
(2007/10/02)
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