50-91-9Relevant articles and documents
Activation of antibacterial prodrugs by peptide deformylase
Wei, Yaoming,Pei, Dehua
, p. 1073 - 1076 (2000)
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.
Floxuridine Oligomers Activated under Hypoxic Environment
Morihiro, Kunihiko,Ishinabe, Takuro,Takatsu, Masako,Osumi, Hiraki,Osawa, Tsuyoshi,Okamoto, Akimitsu
, p. 3340 - 3347 (2021)
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.
Biotransformation of halogenated 2′-deoxyribosides by immobilized lactic acid bacteria
Britos, Claudia N.,Cappa, Valeria A.,Rivero, Cintia W.,Sambeth, Jorge E.,Lozano, Mario E.,Trelles, Jorge A.
, p. 49 - 53 (2012)
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.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
, p. 867 - 876 (2020/01/24)
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.).
FLOXURIDINE SYNTHESIS
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Page/Page column 33-34, (2019/04/11)
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.
Bio-catalytic synthesis of unnatural nucleosides possessing a large functional group such as a fluorescent molecule by purine nucleoside phosphorylase
Hatano, Akihiko,Wakana, Hiroyuki,Terado, Nanae,Kojima, Aoi,Nishioka, Chisato,Iizuka, Yu,Imaizumi, Takuya,Uehara, Sanae
, p. 5122 - 5129 (2019/10/05)
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.
Use of Nucleoside Phosphorylases for the Preparation of Purine and Pyrimidine 2′-Deoxynucleosides
Drenichev, Mikhail S.,Alexeev, Cyril S.,Kurochkin, Nikolay N.,Mikhailov, Sergey N.
, p. 305 - 312 (2018/01/15)
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.).
High purity 5 - fluoro - deoxy uracil nucleoside preparation method
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Paragraph 0154; 0155; 0156; 0157; 0158; 0159, (2017/08/25)
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.
THERMOSTABLE BIOCATALYST COMBINATION FOR NUCLEOSIDE SYNTHESIS
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Paragraph 0090-0091, (2016/08/17)
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.
Biotransformation of halogenated nucleosides by immobilized Lactobacillus animalis 2′-N-deoxyribosyltransferase
Britos, Claudia N.,Lapponi, María José,Cappa, Valeria A.,Rivero, Cintia W.,Trelles, Jorge A.
, p. 91 - 96 (2016/05/10)
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.
