- Efficient synthesis of cladribine via the metal-free deoxygenation
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The efficient synthesis of cladribine via the metal-free deoxygenation was developed. Using (Bu4N)2S2O8/HCO2Na instead of Bu3SnH/AIBN as deoxygenation system, cladribine could be obtained with good yield and even on tens of grams scales. The intermediates and product could be purified by simple work-up process and chromatography was avoided, which showed the good future for industrial applications.
- Xia, Ran,Chen, Lei-Shan
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Read Online
- 2-Substituted dATP Derivatives as Building Blocks for Polymerase-Catalyzed Synthesis of DNA Modified in the Minor Groove
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2′-Deoxyadenosine triphosphate (dATP) derivatives bearing diverse substituents (Cl, NH2, CH3, vinyl, ethynyl, and phenyl) at position 2 were prepared and tested as substrates for DNA polymerases. The 2-phenyl-dATP was not a substrate for DNA polymerases, but the dATPs bearing smaller substituents were good substrates in primer-extension experiments, producing DNA substituted in the minor groove. The vinyl-modified DNA was applied in thiol–ene addition and the ethynyl-modified DNA was applied in a CuAAC click reaction to form DNA labelled with fluorescent dyes in the minor groove.
- Matyasovsky, Ján,Perlikova, Pavla,Malnuit, Vincent,Pohl, Radek,Hocek, Michal
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Read Online
- A concise synthesis of isoguanine 2'-deoxyriboside and its adenine-like triplex formation when incorporated into DNA
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A concise synthesis of 2'-deoxyisoguanosine is achieved whereby 2,6-dichloropurine is glycosylated using the Hoffer sugar to give a pair of beta-configured nucleoside N9/N7 regioisomers that are aminated using methanolic ammonia with concomitant deprotection of the sugar. Following chromatographic separation, pure 2-chloro-2'-deoxyadenosine was isolated as a single isomer. Displacement of the C2 chlorine atom using sodium benzyloxide, followed by hydrogenolysis of the benzyl group, gives 2'-deoxyisoguanosine. Isoguanine was incorporated into DNA by solid supported synthesis using the suitably protected 2-allyloxy-2'-deoxyadenosine phosphoramidite with the allyl group being removed post-oligomerisation under Noyori conditions. DNA melting studies showed isoguanine to exhibit adenine-like triplex formation.
- Walsh, Andrew J.,Schwalbe, Carl H.,Fraser, William
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- Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases
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In the present work, we suggested anion exchange resins in the phosphate form as a source of phosphate, one of the substrates of the phosphorolysis of uridine, thymidine, and 1-(β-D-arabinofuranosyl)uracil (Ara-U) catalyzed by recombinant E. coli uridine (UP) and thymidine (TP) phosphorylases. α-D-Pentofuranose-1-phosphates (PF-1Pis) obtained by phosphorolysis were used in the enzymatic synthesis of nucleosides. It was found that phosphorolysis of uridine, thymidine, and Ara-U in the presence of Dowex 1X8 (phosphate; Dowex-nPi) proceeded smoothly in the presence of magnesium cations in water at 20-50 °C for 54-96 h giving rise to quantitative formation of the corresponding pyrimidine bases and PF-1Pis. The resulting PF-1Pis can be used in three routes: (1) preparation of barium salts of PF-1Pis, (2) synthesis of nucleosides by reacting the crude PF-1Pi with an heterocyclic base, and (3) synthesis of nucleosides by reacting the ionically bound PF-1Pi to the resin with an heterocyclic base. These three approaches were tested in the synthesis of nelarabine, kinetin riboside, and cladribine with good to excellent yields (52-93%).
- Artsemyeva, Julia N.,Buravskaya, Tatiana N.,Esipov, Roman S.,Konstantinova, Irina D.,Litvinko, Natalia M.,Mikhailopulo, Igor A.,Miroshnikov, Anatoly I.,Remeeva, Ekaterina A.
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p. 2607 - 2622
(2020/11/26)
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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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- Enzymatic Synthesis of 2-Deoxyribose 1-Phosphate and Ribose 1 Phosphate and Subsequent Preparation of Nucleosides
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α-Ribose-1-phosphate (Rib-p) and 2-deoxy-α-ribose-1-phosphate (dRib-p) are key intermediates in nucleoside metabolism and are important starting compounds for the enzymatic synthesis of various modified nucleosides. To date, chemical and enzymatic methods allowed the preparation of these compounds in rather low yields (11–37 %). This prevents their widespread use for the enzymatic synthesis of biologically active and practically important nucleosides. Here we propose to use 7-methyl-2′-deoxyguanosine (7-Me-dGuo) and 7-methylguanosine (7-Me-Guo) for the preparation of dRib-p and Rib-p. In this paper, we present the effective preparation of Rib-p and dRib-p starting from readily prepared 7-methylguanosine derivatives via their irreversible enzymatic phosphorolysis in the presence of purine nucleoside phosphorylase. Rib-p and dRib-P are obtained in nearly quantitative yields (HPLC analysis) and 74–96 % yields after their isolation and purification, which is much higher than previously reported.
- Kulikova, Irina V.,Drenichev, Mikhail S.,Solyev, Pavel N.,Alexeev, Cyril S.,Mikhailov, Sergey N.
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supporting information
p. 6999 - 7004
(2019/11/13)
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- Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei
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The use of enzymes for the synthesis of nucleoside analogues offers several advantages over multistep chemical methods, including chemo-, regio- and stereoselectivity as well as milder reaction conditions. Herein, the production, characterization and utilization of a purine nucleoside 2’-deoxyribosyltransferase (PDT) from Trypanosoma brucei are reported. TbPDT is a dimer which displays not only excellent activity and stability over a broad range of temperatures (50–70 °C), pH (4–7) and ionic strength (0–500 mM NaCl) but also an unusual high stability under alkaline conditions (pH 8–10). TbPDT is shown to be proficient in the biosynthesis of numerous therapeutic nucleosides, including didanosine, vidarabine, cladribine, fludarabine and nelarabine. The structure-guided replacement of Val11 with either Ala or Ser resulted in variants with 2.8-fold greater activity. TbPDT was also covalently immobilized on glutaraldehyde-activated magnetic microspheres. MTbPDT3 was selected as the best derivative (4200 IU/g, activity recovery of 22 %), and could be easily recaptured and recycled for >25 reactions with negligible loss of activity. Finally, MTbPDT3 was successfully employed in the expedient synthesis of several nucleoside analogues. Taken together, our results support the notion that TbPDT has good potential as an industrial biocatalyst for the synthesis of a wide range of therapeutic nucleosides through an efficient and environmentally friendly methodology.
- Pérez, Elena,Sánchez-Murcia, Pedro A.,Jordaan, Justin,Blanco, María Dolores,Manche?o, José Miguel,Gago, Federico,Fernández-Lucas, Jesús
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p. 4406 - 4416
(2018/09/14)
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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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- Method for synthesizing cladribine through nitration-chlorination method
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The invention discloses a novel method for synthesizing cladribine through a nitration-chlorination method. According to the method, cheap 6-chloropurine and 1-chloro-2,3,5-tris-O-p-chlorobenzoyl-D-ribose are taken as raw materials, sodium hydride is taken as alkali, acetonitrile is taken as reaction solvent, and a beta isomer is obtained through a high-selectivity reaction; the obtained beta isomer does not need to remove protecting groups, the beta isomer reacts with trifluoromethanesulfonic anhydride after being separated, and nitryl is introduced at the second position; the nitryl is transformed into chlorine atoms in an ethanol solution of NH4Cl; two steps of reactions of protecting group removal and chlorine atom ammonolysis are completed in a methanol solution saturated by ammonia gas, and then the cladribine is obtained through four steps at the total yield of 78%. The method has the advantages that the raw materials are low in cost and easy to obtain, the technology is simple and convenient, the total yield is higher, the cost is low, amplification is easy, expensive reagents and poisonous and harmful heavy metal catalysts are prevented from being used, and when the reaction scale is expanded to the 100-g scale, the yield is not decreased obviously. A novel synthesizing path is supplied to synthesizing of the cladribine, and the potential application prospect is achieved.
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Paragraph 0015; 0020
(2016/10/08)
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- Synthesis of 2,6-dihalogenated purine nucleosides by thermostable nucleoside phosphorylases
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The enzymatic transglycosylation of 2,6-dichloropurine (26DCP) and 6-chloro-2-fluoropurine (6C2FP) with uridine, thymidine and 1-(β-D-arabinofuranosyl)-uracil as the pentofuranose donors and recombinant thermostable nucleoside phosphorylases from G. thermoglucosidasius or T. thermophilus as biocatalysts was studied. Selection of 26DCP and 6C2FP as substrates is determined by their higher solubility in aqueous buffer solutions compared to most natural and modified purines and, furthermore, synthesized nucleosides are valuable precursors for the preparation of a large number of biologically important nucleosides. The substrate activity of 26DCP and 6C2FP in the synthesis of their ribo- and 2′-deoxyribo-nucleosides was closely similar to that of related 2-amino- (DAP), 2-chloro- and 2-fluoroadenines; the efficiency of the synthesis of β-D-arabinofuranosides of 26DCP and 6C2FP was lower vs. that of DAP under similar reaction conditions. For a convenient and easier recovery of the biocatalysts, the thermostable enzymes were immobilized on MagReSyn epoxide beads and the biocatalyst showed high catalytic efficiency in a number of reactions. As an example, 6-chloro-2-fluoro-(β-D-ribofuranosyl)-purine (9), a precursor of various antiviral and antitumour drugs, was synthesized by the immobilized enzymes at 60°C under high substrate concentrations (uridine:purine ratio of 2:1, mol). The synthesis was successfully scaled-up [uridine (2.5 mmol), base (1.25 mmol); reaction mixture 50 mL] to afford 9 in 60% yield. The reaction reveals the great practical potential of this enzymatic method for the efficient production of modified purine nucleosides of pharmaceutical interest.
- Zhou, Xinrui,Szeker, Kathleen,Jiao, Lin-Yu,Oestreich, Martin,Mikhailopulo, Igor A.,Neubauer, Peter
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p. 1237 - 1244
(2015/04/22)
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- Selective Preparations of Purine Nucleosides and Nucleotides: Reagents and Methods
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A process of regiospecific synthesis of N-9 purine nucleoside analogs in either solution or solid phase synthesis is described. The introduction of the sugar moiety or its analogue on to a 6-heteroarylium purine or its mesomeric betaine so that formation of only the N-9 position regioisomers of the purine nucleoside analogs (either D or L enantiomers) is obtained. This regiospecific introduction of the sugar moiety allows the synthesis of purine nucleoside analogs in high yields without formation of the N-7-positional regioisomers, while the 6-heteroaryliums are leaving groups facilitated for nucleophilic displacement. Solid supported 6-heterarylium purine bases can be used for purine based library synthesis and synthesis of nucleotide monophosphates and polyphosphates. Processes for providing novel 6-heteroarylium purines and their corresponding mesomeric betaines for the regiospecific synthesis of N-9 purine nucleoside analogs and nucleotides are described.
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Paragraph 0151
(2016/04/06)
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- Cladribine analogues via O6-(benzotriazolyl) derivatives of guanine nucleosides
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Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.
- Satishkumar, Sakilam,Vuram, Prasanna K.,Relangi, Siva Subrahmanyam,Gurram, Venkateshwarlu,Zhou, Hong,Kreitman, Robert J.,Montemayor, Michelle M. Martínez,Yang, Lijia,Kaliyaperumal, Muralidharan,Sharma, Somesh,Pottabathini, Narender,Lakshman, Mahesh K.
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p. 18437 - 18463
(2015/11/11)
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- A practical synthesis of 2-chloro-2′-deoxyadenosine (Cladribine) from 2′-deoxyadenosine
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A practical synthesis of 2-chloro-2′-deoxyadenosine (Cladribine) from 2′-deoxyadenosine is reported. Treatment of fully protected 2′-deoxyadenosine with 2,2,2-trifluoroacetic anhydride and tetrabutylammonium nitrate gave protected 2-nitro-2′-deoxyadenosine with high yield. 2-Chloro-2′-deoxyadenosine was synthesised in four steps and 44.8% yield after substitution by chloride and deprotection steps.
- Peng, Yao
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p. 213 - 215
(2013/07/25)
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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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- A new synthesis of 2-chloro-2'-deoxyadenosine (Cladribine), CdA)
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A new efficient route for the synthesis of 2-chloro-2';-deoxyadenosine (Cladribine), CdA) has been developed. The key step of this method was selective deprotection of the acetyl group at the 2' position; the 3', 5' acetyl groups were not affected. This can be accomplished efficiently with hydroxylamine hydrochloride and sodium acetate in pyridine. The 2' hydroxyl group was removed by the Barton-McCombie reaction. Using this strategy, CdA was prepared in five steps and 31.0% yields. Copyright Taylor and Francis Group, LLC.
- Xu, Shaohong,Yao, Peng,Chen, Gairong,Wang, Hui
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experimental part
p. 353 - 359
(2011/11/12)
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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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- PROCESS FOR THE PREPARATION OF CLADRIBINE
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A process for the preparation of cladribine of API grade is provided by direct coupling of O-protected 2-deoxy-ribofuranose with silylated 2-chloroadenine followed by deprotection of the resultant protected nucleoside in a separate step and then a purification step. Following the coupling, the desired N-9-glycosylated β-anomer of the nucleoside is directly isolated as a solid from the coupling reaction mixture by filtration in relatively high purity and yield, and it does not require purification.
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Page/Page column 30-31
(2011/04/13)
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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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- Enzymatic transglycosylation of natural and modified nucleosides by immobilized thermostable nucleoside phosphorylases from Geobacillus stearothermophilus
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Natural and modified purine nucleosides have been synthesized using the recombinant thermostable enzymes purine nucleoside phosphorylase II (E. C. 2.4.2.1) and pyrimidine nucleoside phosphorylase (E. C. 2.4.2.2) from Geobacillus stearothermophilus B-2194. The enzymes were produced in recombinant E. coli strains and covalently immobilized on aminopropylsilochrom AP-CPG-170 after heating the cell lysates and the removal of coagulated thermolabile proteins. The resulting preparations of thermostable nucleoside phosphorylases retained a high activity after 20 reuses in nucleoside transglycosylation reactions at 70-75°C with a yield of the target products as high as 96%. Owing to the high catalytic activity, thermal stability, the ease of application, and the possibility of repeated use, the immobilized preparations of thermostable nucleoside phosphorylases are suitable for the production of pharmacologically important natural and modified nucleosides.
- Taran,Verevkina,Feofanov,Miroshnikov
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experimental part
p. 739 - 745
(2010/08/07)
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- Regiospecific and highly stereoselective coupling of 6-(substituted- imidazol-1-yl)purines with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro- pentofuranosyl chloride. Sodium-salt glycosylation in binary solvent mixtures: Improved synthesis of cladribine
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(Chemical Equation Presented) Glycosylation of 6-(substituted-imidazol-1- yl)purine sodium salts with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro- pentofuranosyl chloride proceeds with regiospecific formation of the N9 isomers. Base substrates with lipophilic substituents on the C6-linked imidazole moiety are more soluble in organic solvents, and the solubility is further increased with binary solvent mixtures. Selective solvation also diminishes the extent of anomerization of the chlorosugar. Stirred reaction mixtures of the modified-purine sodium salts generated in a polar solvent and cooled solutions of the protected 2-deoxysugar chloride in a nonpolar solvent give 2′-deoxynucleoside derivatives with N9 regiochemistry and enhanced β/α configuration ratios. Application of the binary-solvent methodology with 2-chloro-6-(substituted-imidazol-1-yl)purine salts in cold acetonitrile and the chlorosugar in cold dichloromethane gives essentially quantitative yields of the N9 isomers of β-anomeric 2′- deoxynucleoside intermediates. Direct ammonolysis (NH3MeOH) of such intermediates or benzylation of the imidazole ring followed by milder ammonolysis of the imidazolium salt gives high yields of the clinical anticancer drug cladribine (2-chloro-2′-deoxyadenosine).
- Zhong, Minghong,Nowak, Ireneusz,Robins, Morris J.
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p. 7773 - 7779
(2007/10/03)
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- METHODS FOR SELECTIVE N-9 GLYCOSYLATION OF PURINES
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A process for providing regiospecific and highly stereoselective synthesis of 9-β anomeric purine nucleoside analogs is described. The introduction of the sugar moiety on to 6-(azolyl)-substituted purine bases is performed so that highly stereoselective formation of the β anomers of only the 9 position regioisomers of the purine nucleoside analogs (either D or L enantiomers) is obtained. This regiospecific and stereoselective introduction of the sugar moiety allows the synthesis of nucleoside analogs, and in particular 2'-deoxy, 3'-deoxy, 2'-deoxy-2'-halo-arabino and 2',3'-dideoxy-2'-halo-threo purine nucleoside analogs, in high yields without formation of the 7-positional regioisomers. Processes for providing novel 6-(azolyl)purines for the regiospecific and highly stereoselective synthesis of 9-β anomeric purine nucleoside analogs are described. The compounds are drugs or intermediates to drugs.
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Page/Page column 61
(2010/11/25)
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- Efficient chemo-enzymatic syntheses of pharmaceutically useful unnatural 2′-deoxynucleosides
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Our chemo-enzymatic method was successfully applied to the synthesis of 2-chloro-2′-deoxyadenosine (CdA, cladribine) in two ways: 1) direct conversion of chemically synthesized 2-deoxy-α-D-ribose 1-phosphate (dRP) to CdA; 2) a two-step route via 9-(2-deoxy-β-D-ribos-1-yl)-2,6- dichloropurine (Cl2Pu-dR, 5). Copyright Taylor & Francis, Inc.
- Komatsu, Hironori,Araki, Tadashi
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p. 1127 - 1130
(2008/02/01)
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- Process for the preparation of 9-beta-anomeric nucleoside analogs
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A process for substantially enhancing the regio and stereoselective synthesis of 9-β-anomeric nucleoside analogs is described. The introduction of the sugar moiety onto a 6-substituted purine base was preformed so that only the 9-β-D- or L-purine nucleoside analogs were obtained. This regio and stereoselective introduction of the sugar moiety allows the synthesis of nucleoside analogs and in particular 2′-deoxy, 3′-deoxy, 2′-deoxy-2′-β-fluoro and 2′,3′-dideoxy-2′-β-fluoro purine nucleoside analogs in high yield without virtually any formation of the 7-positional isomers. The compounds are drugs or intermediates to drugs.
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- Efficient syntheses of 2-chloro-2′-deoxyadenosine (cladribine) from 2′-deoxyguanosine
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We report efficient syntheses of the clinical agent cladribine (2-chloro-2′-deoxyadenosine, CldAdo), which is the drug of choice against hairy-cell leukemia and other neoplasms, from 2′-deoxyguanosine. Treatment of 3′,5′-di-O-acetyl- or benzoyl-2′-deoxyguanosine (1) with 2,4,6-triisopropyl- or 4-methylbenzenesulfonyl chloride gave high yields of the 6-O-arylsulfonyl derivatives 2 or 2′b. Deoxychlorination at C6 of 1 also proceeded to give the 2-amino-6-chloropurine derivative 5 in excellent yields. The nonaqueous diazotization/chloro dediazoniation (acetyl chloride/benzyltriethylammonium nitrite) of 2, 2′b, and 5 gave the 2-chloropurine derivatives 3, 3′b, and 6, respectively. The selective ammonolysis at C6 (arylsulfonate with 3 or chloride with 6) and accompanying deprotection of the sugar moiety gave CldAdo (64-75% overall yield from 1).
- Janeba, Zlatko,Francom, Paula,Robins, Morris J.
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p. 989 - 992
(2007/10/03)
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- Azido/Tetrazole Tautomerism in 2-Azidoadenine β -D-Pentofuranonucleoside Derivatives
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The β-D-ribofuranoside derivative of 2-azidoadenine and its 2′-deoxy-, 2′,3′-dideoxy- and 2′,3′ -dideoxy-2′,3′-didehydro counterparts have been synthesized. All these compounds were obtained through the preparation of their 2-chloro precursors. These were converted into their 2-hydrazino derivatives, which upon treatment with sodium nitrate in acid medium gave the target nucleosides. The azido/tetrazole tautomerism observed in such nucleoside analogues was studied in detail. The compounds were also tested for their activity against HIV and HBV, but did not show significant antiviral effects. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Lioux, Thierry,Gosselin, Gilles,Mathe, Christophe
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p. 3997 - 4002
(2007/10/03)
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- A universal biocatalyst for the preparation of base- and sugar-modified nucleosides via an enzymatic transglycosylation
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The E. coli BMT-4D/1A cells have been selected according to Munch-Petersen et al. They carry two regulatory mutations (cytR and deoR) and are able to synthesize constitutively nucleoside-catabolizing enzymes, e.g., cells that possess high UPase and PNPase activities. The cells have been cross-linked by glutaraldehyde to afford a biocatalyst that retained high UPase and PNPase activities and was comfortable for repeated use. An incubation of 2′-deoxyguanosine (1) and 2-chloroadenine (2) (molar ratio 3:1) in K-phosphate buffer (10 mM; pH 7.0) in the presence of the biocatalyst at 65° for 7 h resulted in quantitative transformation of 2 into 2-chloro-2′-deoxyadenosine (4; cladribine) that was isolated in 81% yield (Scheme 1). Similarly, the reaction of guanosine (5) and 1,2,4-triazole-3-carboxamide (6) (molar ratio 1:1) in K-phosphate buffer (10mM; pH 7.0) in the presence of the biocatalyst at 60° for 30h led to the formation of 1-(β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (8; ribavirin) in 90-92% yield (67-70% isolated yield) (Scheme 2).
- Barai, Vladimir N.,Zinchenko, Anatoli I.,Eroshevskaya, Ludmilla A.,Kalinichenko, Elena N.,Kulak, Tamara I.,Mikhailopulo, Igor A.
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p. 1901 - 1908
(2007/10/03)
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- Method for the production of 2-chloro-2' -deoxyadenosine (cladribine) and its 3,5-di-O-p-toluoyl derivative
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A process for the production of cladribine, 2-chloro-2′-deoxyadenosine, is provided which involves the direct glycosylation of 2-chloro-6-aminopurine with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythropentofuranose. The process is carried out by first forming the sodium salt of 2-chloro-6-aminopurine and allowing the sodium salt to react with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythropentofuranose in the presence of a moderately polar solvent such as acetone. The final product, cladribine, is produced by removal of the p-toluoyl groups by the action of methanolic ammonia or methanolic sodium methoxide.
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- LIPID CLEAVAGE ENZYME
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A membranous enzyme not yet described in the state-of-the-art can be extracted from cellular membrane fractions of blood leukocytes or monocytes/macrophages. Also disclosed is the use of substrates of this enzyme to prepare medicaments that contain these substrates as pharmaceutical active substance. These medicaments are useful to direct pharmacologically active substances to target cells and to enrich target cells with said substances. Also disclosed are in-vitro research systems containing this enzyme used to detect other substrates of this enzyme.
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- Specific lipid conjugates to nucleoside diphosphates and their use as drugs
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The present invention concerns new phospholipid derivatives of nucleosides of the general formula (I) in which R1represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times; R2can represent a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can optionally be substituted once or several times; m is 2 or 3; A can represent a methylene group or an oxygen; Nuc can be a nucleoside or a residue derived from a nucleoside derivative; and tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases as well as pharmaceutical preparations containing these compounds.
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- Process for the production of 2-halo-6-aminopurine derivatives
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A novel process for preparing 2-halo-6-aminopurine derivatives and their analogs is disclosed. The method comprises halogenation of 2,6-diaminopurine derivatives at the C-2 position in a specific combination of aprotic polar and nonpolar organic solvents to give the corresponding halogenated derivatives.
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- Process for the production of asymmetrical phosphoric acid diesters
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The present invention concerns a process for the production of asymmetrical phosphoric acid diesters. The process is characterized in that a phosphoric acid ester is condensed with a compound containing hydroxy groups in the presence of an arylsulfonic acid chloride and an organic base, the residue of evaporation is stirred out with an organic solvent after the hydrolysis, the arylsulfonic acid pyridine salt which forms is nearly completely crystallized and recycled, the lipid derivative that is formed is precipitated as a sparingly soluble salt by addition of a solution containing alkaline-earth ions and isolated, the sparingly soluble salt is isolated as the free acid in an organic solvent by suspension in a water-immiscible organic solvent and a dilute aqueous mineral acid, the crude product is purified if desired, by means of preparative chromatography on a RP phase and subsequently the free acid is converted if desired into any desired salt.
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- The N-7 regioisomer of 2-chloro-2'-deoxyadenosine: synthesis, crystal structure, conformation, and stability
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The nucleoside 6-amino-2-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-purine 7 is readily accessible in two steps from 2,6-dichloropurine.The crystal structure of this unusual nucleoside reveals a bifurcated intramolecular hydrogen bond from the amino group to the O-5' with a weaker branch to the O-4' which imposes a syn glycosidic torsion angle: χ=67.0 deg.Semi-empirical calculations using AM1 parameters and optimisation of atomic co-ordinates derived from the crystal structure of 7 suggest that the molecule can adopt either anti or syn conformations with a slight preference for anti by 0.4 kcal mol-1 in heat of formation (ΔHf).NOE experiments in (CD3)2SO solution support the theoretical results indicating the presence of both syn and anti conformations and that the anti population is marginally favoured.The antileukaemic agent 2-chloro-2'-deoxyadenosine (6), the N-9 regioisomer of 7, was shown to be 9.6 kcal mol-1 more stable than 7.The increased stability of 6 over 7 seems attributable mainly to the relative stability of the aglycon tautomers 8 and 9, the energy difference between thase being 6.7 kcal mol-1 in favour of the 9H tautomer 8.Likewise, removal of the 2-chloro substituent has little effect on the tautomerism. Keywords: N-7 nucleoside; X-ray structure; semi-empirical; Conformation; NOE
- Worthington, Victoria L.,Fraser, William,Schwalbe, Carl H.
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p. 275 - 284
(2007/10/03)
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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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- Intermediates useful in a synthesis of 2-chloro-2'-deoxyadenosine
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This invention relates to a novel process for preparing 2-chloro-2'-deoxyadenosine (2-CdA) having the following formula STR1 from a compound of the following formula STR2 The invention also relates to intermediates which are useful in preparing 2-CdA. The compound 2-CdA is useful as an antileukemic agent, i.e., in treating leukemias, such as hairy cell leukemia.
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- Synthesis of 2'-Deoxytubercidin, 2'-Deoxyadenosine, and Related 2'-Deoxynucleosides via a Novel Direct Stereospecific Sodium Salt Glycosylation Procedure
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A general and stereospecific synthesis has been developed for the direct preparation of 2'-deoxy-β-D-ribofuranosylpurine analogues including 2'-deoxyadenosine derivatives.The reaction of the sodium salt of 4-chloropyrrolopyrimidine (4) or 2,4-dichloropyrrolopyrimidine (1) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose (25) provided the corresponding N-1,2'-deoxy-β-D-ribofuranosyl blocked derivatives (5 and 2) which, on ammonolysis, gave 2'-deoxytubercidin (6) and 2-chloro-2'-deoxytubercidin (3), respectively, in good yield.This glycosylation also readily proceeds in the presence of a 2-methylthio group.Application of this glycosylation procedure to 4,6-dichloroimidazopyridine (10), 6-chloropurine (16), 2,6-dichloropurine (13), and 4-chloropyrazolopyrimidine (19) gave 2-chloro-2'-deoxy-3-deazaadenosine (12), 2-'-deoxyadenosine (18), 2-chloro-2'-deoxyadenosine (15), and 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazolopyrimidine (21), respectively.Similarly, glycosylation and ammonolysis of 4,6-dichloro-1H-pyrrolopyridine (22) gave 4,6-dichloro-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyridine (24).This stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C-1 carbon of 25.
- Kazimierczuk, Zygmunt,Cottam, Howard B.,Revankar, Ganapathi R.,Robins, Roland K.
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p. 6379 - 6382
(2007/10/02)
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