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The aminomethylation of adenine, cytosine and guanine
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Sloan,Siver
p. 3997 - 4001
(1984)
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A facile and effective synthesis of lamivudine 5′-diphosphate
We report on the first solution synthesis of lamivudine 5′-diphosphate in both high yield and purity. Efficient synthesis of lamivudine 5′-monophosphate was obtained through lamivudine H-phosphonate oxidation by (-)-(8,8-dichlorocamphorylsulfonyl)oxaziridine. Diphosphorylation was performed by nucleophilic substitution of the phosphorimidazolate derivative of lamivudine. HPLC coupled with UV or MS detection was found to be an invaluable tool for the follow-up of phosphorylation reactions.
Roy, Béatrice,Lefebvre, Isabelle,Puy, Jean-Yves,Périgaud, Christian
p. 1250 - 1252
(2011)
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2'-C-cyano-2'-deoxy-1-β-D-arabinofuranosyl-cytosine (CNDAC): A mechanism-based DNA-strand-breaking antitumor nucleoside
The antitumor mechanism of action of 2'-C-cyano-2'-deoxy-1-β-D- arabinofuranosyl (CNDAC) has been examined. CNDAC was designed as a potentially DNA-self-strand-breaking nucleoside. It had potent antitumor effects against various solid tumors in vitro as well as in vivo. Using a chain-extension method with Vent (exo-) DNA polymerase and a short primer/template system, we found that 5'-triphosphate of CNDAC (CNDACTP) was incorporated into the primer at a site opposite a guanine residue in the template. After further chain-extension reaction of the primer containing CNDAC at the 3'-terminus, chain elongation was not observed. Therefore, CNDACTP appeared to act as a chain-terminator. Analyses of the structure of the 3'-terminus in the primer revealed 2'-C-cyano-2',3'-didehydro-2',3'- dideoxycytidine (ddCNC) together with CNDAC and 2'-C-cyano-2'-deoxy-1-β-D- ribofuranosylcytosine (CNDC). The existence of ddCNC in the 3'-end of the primer would be due to the self-strand-break by the nucleotide incorporated next to CNDAC. We also found that CNDAC was epimerized to CNDC in near- neutral to alkaline media. Therefore, CNDC found in the primer was epimerized after incorporation of CNDACTP into the primer. We also described the metabolism of CNDAC.
Matsuda,Azuma
p. 461 - 471
(1995)
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Nucleosides and Nucleotides. 141. Chemical Stability of a new Antitumor Nucleoside, 2'-C-Cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine in Alkaline Medium: Formation of 2'-C-Cyano-2;-deoxy-1-β-D-ribo-pentofuranosylcytosine and Its Antitumor Activity.
We have designed 2'-C-Cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) as a potential mechanism-based DNA-strand-breaking nucleoside, which showed potent tumor cell growth inhibitory activity against various human tumor cell lines in vitro and in vivo.When measuring the pKa of the 2'α-proton of CNDAC, we found that CNDAC epimerized to 2'-C-cyano-2'-deoxy-1-β-D-ribo-pentofuranosylcytosine (CNDC) with concomitant degradation of both CNDAC and CNDC to cytosine and 1,4-anhydro-2-C-cyano-2-deoxy-D-erythro-pent-1-enitol.Kinetic analysis of these reactions showed that abstraction of the acidic 2'-proton of CNDAC and CNDC initiated the reactions, which quickly reached an equilibrium.In the equilibrium, a concentration ratio of CNDAC and CNDC was about 3:5.Concomitant degradation of these nucleosides was found to be rather slow.Deuterium incorporation experiments with CNDAC in a D2O buffer suggested the mechanism of the β-elimination reactions is an E1cB type.These epimerization and degradation reactions were found even in neutral conditions (pH 7.5) and also occurred in RPMI 1640 cell culture medium.The discovewry of which nucleoside possesses the predominate tumor cell growth inhibitory activity was important.While both nucleosides showed potent tumor cell growth inhibitory activity against three human tumor cell lines (colon carcinoma WiDr, small cell lung carcinoma SBC-5, and stomach carcinoma MKN-74 cells) in 48 h of incubation, in 20 min of incubation, CNDAC was 11-50 times more effective than CNDC.In vivo antileukemic activity of these nucleosides against a mouse P388 model, CNDAC was obviously superior to CNDC.Therefore, tumor cell growth inhibitory activity of CNDC could be related to the quantity of CNDAC produced in the tumor cells by the equilibrium initiated by the abstraction of the acidic 2'-proton of CNDC.
Azuma, Atsushi,Hanaoka, kenji,Kurihara, Atsushi,Kobayashi, Tomowo,Miyauchi, Seiji,et al.
p. 3391 - 3397
(1995)
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Homochiral crystal generation: Via sequential dehydration and Viedma ripening
1,2-Bis(N-benzoyl-N-methylamino)benzene (2) forms centrosymmetric hydrate crystals (2·xH2O) and non-centrosymmetric anhydrous crystals. Dehydration of this hydrate (30 min at 140 °C) resulted in the formation of chiral crystals (i.e. a physical racemate of the conglomerate crystals) as verified using solid-state circular dichroism and powder X-ray diffraction. Subsequent attrition-enhanced deracemization, also known as Viedma ripening, was used to obtain homochiral crystals of 2 within 5 h.
Sivakumar, Reajean,Askari, Mohammad S.,Woo, Simon,Madwar, Carolin,Ottenwaelder, Xavier,Bohle, D. Scott,Cuccia, Louis A.
p. 4277 - 4280
(2016)
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Evidence for C-1' hydrogen abstraction from modified oligonucleotides by Fe-bleomycin
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Duff,De Vroom,Geluk,Hecht,Van Der Marel,Van Boom
p. 3350 - 3351
(1993)
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Kutscher
p. 170
(1903)
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TET-Like Oxidation in 5-Methylcytosine and Derivatives: A Computational and Experimental Study
The epigenetic marker 5-methylcytosine (5mC) is an important factor in DNA modification and epigenetics. It can be modified through a three-step oxidation performed by ten-eleven-translocation (TET) enzymes and we have previously reported that the iron(IV)-oxo complex [Fe(O)(Py5Me2H)]2+ (1) can oxidize 5mC. Here, we report the reactivity of this iron(IV)-oxo complex towards a wider scope of methylated cytosine and uracil derivatives relevant for synthetic DNA applications, such as 1-methylcytosine (1mC), 5-methyl-iso-cytosine (5miC) and thymine (T/5mU). The observed kinetic parameters are corroborated by calculation of the C?H bond energies at the reactive sites which was found to be an efficient tool for reaction rate prediction of 1 towards methylated DNA bases. We identified oxidation products of methylated cytosine derivatives using HPLC-MS and GC-MS. Thereby, we shed light on the impact of the methyl group position and resulting C?H bond dissociation energies on reactivity towards TET-like oxidation.
Jonasson, Niko S. W.,Jan?en, Rachel,Menke, Annika,Zott, Fabian L.,Zipse, Hendrik,Daumann, Lena J.
p. 3333 - 3340
(2021/09/25)

Sources of 2,5-diaminoimidazolone lesions in DNA damage initiated by hydroxyl radical attack
The present study reports radiation-chemical yields of 2.5-diaminoimidazolone (Iz) derivatives in X-irradiated phosphate-buffered solutions of guanosine and double-stranded DNA. Various gassing conditions (air, N20/O2 (4:1), N2O, vacuum) were employed to elucidate the contribution of several alternative pathways leading to Iz in reactions initiated by hydroxyl radical attack on guanine. In all systems, Iz was identified as the second by abundance guanine degradation product after 8-oxoguanine, formed in 1:5 (guanosine) and 1:3.3 (DNA) ratio to the latter in air-saturated solutions. Experimental data strongly suggest that the addition of molecular oxygen to the neutral guanine radical G(-H)? plays a major in Iz production in oxygenated solutions of double-stranded DNA while in other systems it may compete with recombination of G(-H)? with superoxide and/or alkyl peroxyl radicals. The production of Iz through hydroxyl radical attack on 8-oxoguanine was also shown to take place although the chemical yield of Iz (ca 6%) in this process is too low to compete with the other pathways. The linearity of Iz accumulation with dose also indicates a negligible contribution of this channel to its yield in all systems.
Thomas, Caroline Suzanne,Pollard, Hannah Catherine,Razskazovskiy, Yuriy,Roginskaya, Marina
p. 517 - 524
(2020/09/07)

Monitoring the reactivity of formamide on amorphous SiO2 by in-situ UV-Raman spectroscopy and DFT modeling
Formamide has been recognized in the literature as a key species in the formation of the complex molecules of life, such as nucleobases. Furthermore, several studies reported the impact of mineral phases as catalysts for its decomposition/polymerization processes, increasing the conversion and also favoring the formation of specific products. Despite the progresses in the field, in situ studies on these mineral-catalyzed processes are missing. In this work, we present an in situ UV-Raman characterization of the chemical evolution of formamide over amorphous SiO2 samples, selected as a prototype of silicate minerals. The experiments were carried out after reaction of formamide at 160 ?C on amorphous SiO2 (Aerosil OX50) either pristine or pre-calcined at 450 ?C, to remove a large fraction of surface silanol groups. Our measurements, interpreted on the basis of density functional B3LYP-D3 calculations, allow to assign the spectra bands in terms of specific complex organic molecules, namely, diaminomaleonitrile (DAMN), 5-aminoimidazole (AI), and purine, showing the role of the mineral surface on the formation of relevant prebiotic molecules.
Balucani, Nadia,Bonino, Francesca,Martra, Gianmario,Pantaleone, Stefano,Signorile, Matteo,Ugliengo, Piero
(2020/05/28)

A one-pot, water compatible synthesis of pyrimidine nucleobases under plausible prebiotic conditions
Herein, we report a new prebiotically plausible pathway towards a pyrimidine nucleobase in continuous manner. The route involves simultaneous methylation and carbamoylation of cyanoacetylene-derived α,β-unsaturated thioamide with N-methyl-N-nitrosourea (MNU) in aqueous media. This provides S-methylpyrimidinone in one-pot, which can be converted into a variety of 4-substituted pyrimidine nucleobases including cytosine and uracil.
Okamura, Hidenori,Becker, Sidney,Tiede, Niklas,Wiedemann, Stefan,Feldmann, Jonas,Carell, Thomas
supporting information
p. 1939 - 1942
(2019/05/02)

Dehalogenation of Halogenated Nucleobases and Nucleosides by Organoselenium Compounds
Halogenated nucleosides, such as 5-iodo-2′-deoxyuridine and 5-iodo-2′-deoxycytidine, are incorporated into the DNA of replicating cells to facilitate DNA single-strand breaks and intra- or interstrand crosslinks upon UV irradiation. In this work, it is shown that the naphthyl-based organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based nucleosides, such as 5-X-2′-deoxyuridine and 5-X-2′-deoxycytidine (X=Br or I). The rate of deiodination was found to be significantly higher than that of the debromination for both nucleosides. Furthermore, the deiodination of iodo-cytidines was found to be faster than that of iodo-uridines. The initial rates of the deiodinations of 5-iodocytosine and 5-iodouracil indicated that the nature of the sugar moiety influences the kinetics of the deiodination. For both the nucleobases and nucleosides, the deiodination and debromination reactions follow a halogen-bond-mediated and addition/elimination pathway, respectively.
Mondal, Santanu,Mugesh, Govindasamy
p. 1773 - 1780
(2019/01/10)

Silica Metal Oxide Vesicles Catalyze Comprehensive Prebiotic Chemistry
It has recently been demonstrated that mineral self-assembled structures catalyzing prebiotic chemical reactions may form in natural waters derived from serpentinization, a geological process widespread in the early stages of Earth-like planets. We have s
Mattia Bizzarri, Bruno,Botta, Lorenzo,Pérez-Valverde, Maritza Iveth,Saladino, Raffaele,Di Mauro, Ernesto,García-Ruiz, Juan Manuel
p. 8126 - 8132
(2018/05/29)

Selective aqueous acetylation controls the photoanomerization of α-cytidine-5′-phosphate
Nucleic acids are central to information transfer and replication in living systems, providing the molecular foundations of Darwinian evolution. Here we report that prebiotic acetylation of the non-natural, but prebiotically plausible, ribonucleotide α-cy
Fernández-García, Christian,Grefenstette, Natalie M.,Powner, Matthew W.
supporting information
p. 4850 - 4853
(2018/05/23)

Method for synthesizing cytosine
The invention discloses a method for synthesizing cytosine, and belongs to the field of nucleoside synthesis in organic chemistry. The method comprises the following reaction steps: reacting a raw material 3-hydroxyacrylonitrile sodium salt with ammonia to generate aminoacrylonitrile, reacting the aminoacrylonitrile with carbonate ester to obtain an intermediate, and reacting the intermediate withammonia in the presence of DBU or DBN to generate cytosine. Only a three-step reaction is carried out in the whole process, so the use of urea is avoided, and the process conditions are suitable forindustrial amplification.
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Paragraph 0034; 0036

(2018/03/26)

Difluoronucleoside antimetabolite anticancer drug for destroying cell replication
The invention provides a difluoronucleoside antimetabolite anticancer drug for destroying cell replication as well as preparation and application of pharmaceutical composition of the antimetabolite anticancer drug. The chemical structural formula of the difluoronucleoside antimetabolite anticancer drug for destroying cell replication is shown as (A) in the description. The drug is an important anticancer drug, has the characteristic of wide antitumor spectrum, shows better anticancer activity in various tumors such as non-small cell lung cancer, breast cancer, pancreatic cancer and the like, and is one of the first choices for treatment of the non-small cell lung cancer and also one of the first choices for chemotherapy of pancreatic cancer.
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Paragraph 0035; 0047; 0054; 0057; 0060

(2018/09/13)

Method for synthesizing cytosine
The invention discloses a method for synthesizing cytosine. The method comprises the following steps: taking charcoal and carbon dioxide as raw materials, and obtaining mixed gas through one-pot reaction; directly reacting with acetonitrile under the action of alkali without separation; finally condensing and cyclizing with urea to obtain the cytosine. The method disclosed by the invention has the benefits that the raw materials are cheap and easy to obtain, the use of an expensive, toxic and harmless reagent is avoided, the use of dangerous and corrosive operation steps is avoided, and the environmental protection and the industrial production are facilitated. The method disclosed by the invention provides a new synthetic pathway for the cytosine and has a potential application prospect.
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Paragraph 0019; 0022; 0025; 0028; 0030

(2017/07/20)

Cytosine Radical Cations: A Gas-Phase Study Combining IRMPD Spectroscopy, UVPD Spectroscopy, Ion–Molecule Reactions, and Theoretical Calculations
The radical cation of cytosine (Cyt.+) is generated by dissociative oxidation from a ternary CuII complex in the gas phase. The radical cation is characterized by infrared multiple photon dissociation (IRMPD) spectroscopy in the fingerprint region, UV/Vis photodissociation (UVPD) spectroscopy, ion–molecule reactions, and theoretical calculations (density functional theory and ab initio). The experimental IRMPD spectrum features diagnostic bands for two enol-amino and two keto-amino tautomers of Cyt.+ that are calculated to be among the lowest energy isomers, in agreement with a previous study. Although the UVPD action spectrum can also be matched to a combination of the four lowest energy tautomers, the presence of a nonclassical distonic radical cation cannot be ruled out. Its formation is, however, unlikely due to the high energy of this isomer and the respective ternary CuII complex. Gas-phase ion–molecule reactions showed that Cyt.+ undergoes hydrogen-atom abstraction from 1-propanethiol, radical recombination reactions with nitric oxide, and electron transfer from dimethyl disulfide.
Lesslie, Michael,Lawler, John T.,Dang, Andy,Korn, Joseph A.,Bím, Daniel,Steinmetz, Vincent,Ma?tre, Philippe,Ture?ek, Frantisek,Ryzhov, Victor
p. 1293 - 1301
(2017/05/26)

Process for synthesis of cytosine
The invention discloses a process for synthesizing cytosine. A 3-hydroxyacrylonitrile compound and an O-methylisourea compound or an S-methylisothiourea compound or an S-ethylisothiourea compound or an S-benzylisothiourea compound are used as raw materials. The process comprises the steps of adding a catalyst and an organic solvent into a reaction kettle, stirring, and then adding the raw materials; heating the mixture to be 50-90 DEG C, and reacting for 8-12 hours; evaporating the solvent to obtain an intermediate; adding concentrated hydrochloric acid into the intermediate, heating to be 70-100 DEG C, and preserving the heat for 1-2 hours; adding water, performing hot filtration, and cooling the obtained filtrate to room temperature; dripping a sodium hydroxide solution into the filtrate to adjust the pH value to be 7-7.5, and cooling to 10-15 DEG C; filtering after cooling, washing, and drying to obtain the cytosine. The process has the advantages that the process steps are simple, the production period is short, and the cost is low; the conversion rate of the raw materials is high, and the synthesized product is good in quality and high in yield, so that the process is suitable for industrialized production.
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Paragraph 0010; 0018

(2017/05/05)

A method for synthesis of cytosine
The invention discloses a synthesis method of cytosine. According to the method, ethyl cyanoacetate, urea and triethyl orthoformate are utilized as raw materials, ethyl 3-cyano-2-ureido-acrylate, 5-ethoxycarbonyl cytosine, and 5-carboxyl cytosine are sequentially synthesized, decarboxylation is performed to synthesize cytosine and refining, correction, perfection and other various process steps are sequentially performed. Therefore, the yield of the synthesis method is high, the highest total yield can achieve 75.14%, the comprehensive benefits are finally improved and the method has the advantages of simplicity in operation, small difficulty in actual production and convenience in large-scale application.
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Paragraph 0114; 0115

(2017/03/22)

Process for preparation of cytosine
The invention discloses a technology for preparing cytosine. The technology comprises the following steps: selecting a 3-hydroxyl acrylonitrile sodium salt and urea or a urea alkali metal salt as raw materials; firstly, feeding a catalyst and an organic solvent to a reaction kettle in preparation; sequentially adding 3-hydroxyl acrylonitrile sodium salt and urea or urea alkali metal salt after evenly agitating; heating up to 40-90 DEG C and carrying out cyclization reaction for 6-10 hours, so as to obtain cyclization reaction liquid; evaporating out a solvent in the cyclization reaction liquid; adding water to the residue to dissolve; dropwise adding a hydrochloric acid to adjust the pH value; cooling when the pH achieves 7.0-7.5; filtering, washing and baking after cooling to 10-15 DEG C, so as to obtain the cytosine. The technology has the advantages of being simpler in processing step, short in production cycle, low in cost, and high in raw material conversion rate, the labor operation and energy consumption are greatly reduced, and the synthesized product is good in quality, high in yield, convenient in post-treatment, and applicable to industrial production.
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Paragraph 0016

(2017/05/10)

Method for synthesis of cytosine
The invention discloses a synthesis method of cytosine. The preparation process comprises the following steps: selecting 3-hydroxy acrylonitrile sodium salt and thiourea as raw materials; when preparing, adding a catalyst and an organic solvent to a reaction kettle, uniformly stirring, and sequentially adding the 3-hydroxy acrylonitrile sodium salt and the thiourea; raising temperature to 50-90 DEG C and carrying out a cyclization reaction for 6-10 hours to obtain a cyclization reaction solution; evaporating out the solvent in the cyclization reaction solution, and adding water and hydrochloric acid to obtain an intermediate product solution; dropping hydrogen peroxide to the intermediate product solution, raising temperature to 60-90 DEG C and preserving heat for 18-24 hours; regulating pH value through a sodium hydroxide solution, and cooling to 10-15 DEG C when the pH value is 7.0-7.5; and after cooling, filtering, washing and drying to obtain the cytosine. The synthesis method disclosed by the invention has the advantages that the process is simple in step, short in production cycle and low in cost; moreover, a raw material conversion rate is high, and the synthesized product is good in quality, high in yield, convenient in post-treatment and applicable to industrial production.
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Paragraph 0019

(2017/04/07)

A Global Scale Scenario for Prebiotic Chemistry: Silica-Based Self-Assembled Mineral Structures and Formamide
The pathway from simple abiotically made organic compounds to the molecular bricks of life, as we know it, is unknown. The most efficient geological abiotic route to organic compounds results from the aqueous dissolution of olivine, a reaction known as serpentinization (Sleep, N.H., et al. (2004) Proc. Natl. Acad. Sci. USA 101, 12818-12822). In addition to molecular hydrogen and a reducing environment, serpentinization reactions lead to high-pH alkaline brines that can become easily enriched in silica. Under these chemical conditions, the formation of self-assembled nanocrystalline mineral composites, namely silica/carbonate biomorphs and metal silicate hydrate (MSH) tubular membranes (silica gardens), is unavoidable (Kellermeier, M., et al. In Methods in Enzymology, Research Methods in Biomineralization Science (De Yoreo, J., Ed.) Vol. 532, pp 225-256, Academic Press, Burlington, MA). The osmotically driven membranous structures have remarkable catalytic properties that could be operating in the reducing organic-rich chemical pot in which they form. Among one-carbon compounds, formamide (NH2CHO) has been shown to trigger the formation of complex prebiotic molecules under mineral-driven catalytic conditions (Saladino, R., et al. (2001) Biorganic & Medicinal Chemistry, 9, 1249-1253), proton irradiation (Saladino, R., et al. (2015) Proc. Natl. Acad. Sci. USA, 112, 2746-2755), and laser-induced dielectric breakdown (Ferus, M., et al. (2015) Proc Natl Acad Sci USA, 112, 657-662). Here, we show that MSH membranes are catalysts for the condensation of NH2CHO, yielding prebiotically relevant compounds, including carboxylic acids, amino acids, and nucleobases. Membranes formed by the reaction of alkaline (pH 12) sodium silicate solutions with MgSO4 and Fe2(SO4)3·9H2O show the highest efficiency, while reactions with CuCl2·2H2O, ZnCl2, FeCl2·4H2O, and MnCl2·4H2O showed lower reactivities. The collections of compounds forming inside and outside the tubular membrane are clearly specific, demonstrating that the mineral self-assembled membranes at the same time create space compartmentalization and selective catalysis of the synthesis of relevant compounds. Rather than requiring odd local conditions, the prebiotic organic chemistry scenario for the origin of life appears to be common at a universal scale and, most probably, earlier than ever thought for our planet.
Saladino, Raffaele,Botta, Giorgia,Bizzarri, Bruno Mattia,Di Mauro, Ernesto,Garcia Ruiz, Juan Manuel
p. 2806 - 2811
(2016/06/01)

Multimodal Vacuum-Assisted Plasma Ion (VaPI) Source with Transmission Mode and Laser Ablation Sampling Capabilities
We have developed a multimodal ion source design that can be configured on the fly for various analysis modes, designed for more efficient and reproducible sampling at the mass spectrometer atmospheric pressure (AP) interface in a number of different applications. This vacuum-assisted plasma ionization (VaPI) source features interchangeable transmission mode and laser ablation sampling geometries. Operating in both AC and DC power regimes with similar results, the ion source was optimized for parameters including helium flow rate and gas temperature using transmission mode to analyze volatile standards and drug tablets. Using laser ablation, matrix effects were studied, and the source was used to monitor the products of model prebiotic synthetic reactions. [Figure not available: see fulltext.]
Keelor, Joel D.,Farnsworth, Paul B.,L. Weber, Arthur,Abbott-Lyon, Heather,Fernández, Facundo M.
p. 897 - 907
(2016/05/02)

Preparation method of cytosine intermediate 3,3-diethoxypropionitrile
The invention discloses a preparation method of cytosine intermediate 3,3-diethoxypropionitrile. The preparation method comprises following steps: 1) acetonitrile is taken as a raw material, and is reacted with tert-butyl hydroperoxide (TBHP) in the presence of a catalyst, and an obtained product and carbon monoxide are subjected to carbonylation reaction so as to obtain nitrile acetaldehyde; and step 2, nitrile acetaldehyde is reacted with ethanol in the presence of acid alcohol of a catalytic amount so as to obtain 3,3-diethoxypropionitrile. Obtained 3,3-diethoxypropionitrile can be subjected to condensation reaction with urea so as to prepare cytosine, synthesis effect is excellent, and the quality of obtained cytosine is high. Reaction mechanism of the preparation method is different from reaction mechanism of the prior art in which acetonitrile hydrogen protons are captured by strong base; in the preparation method, acetonitrile hydrogen protons are captured via free radical reaction so as to obtain acetonitrile free radicals; the acetonitrile free radicals are subjected to carbonylation reaction with carbon monoxide so as to obtain nitrile acetaldehyde directly; and nitrile acetaldehyde is transformed into 3,3-diethoxypropionitrile in the presence of acid alcohol of a catalytic amount.
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Paragraph 0028; 0029

(2017/02/17)

Structure of the N-glycosidase MilB in complex with hydroxymethyl CMP reveals its Arg23 specifically recognizes the substrate and controls its entry
5-Hydroxymethylcytosine (5hmC) is present in T-even phage and mammalian DNA as well as some nucleoside antibiotics, including mildiomycin and bacimethrin, during whose synthesis 5hmC is produced by the hydrolysis of 5-hydroxymethyl cytidine 5'-monophosphate (hmCMP) by an N-glycosidase MilB. Recently, the MilB-CMP complex structure revealed its substrate specificity for CMP over dCMP. However, hmCMP instead of CMP is the preferred substrate for MilB as supported by that its KM for CMP is ～27-fold higher than that for hmCMP. Here, we determined the crystal structures of MilB and its catalytically inactive E103A mutant in complex with hmCMP. In the structure of the complex, Phe22 and Arg23 are positioned in a cage-like active site resembling the binding pocket for the flipped 5-methylcytosine (5mC) in eukaryotic 5mC-binding proteins. Van der Waals interaction between the benzene ring of Phe22 and the pyrimidine ring of hmCMP stabilizes its binding. Remarkably, upon hmCMP binding, the guanidinium group of Arg23 was bent ～65° toward hmCMP to recognize its 5-hydroxymethyl group, inducing semi-closure of the cage-like pocket. Mutagenesis studies of Arg23 and bioinformatics analysis demonstrate that the positively charged Arg/Lys at this site is critical for the specific recognition of the 5-hydroxymethyl group of hmCMP. The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
Zhao, Gong,Wu, Geng,Zhang, Yan,Liu, Guang,Han, Tiesheng,Deng, Zixin,He, Xinyi
p. 8115 - 8124
(2014/07/22)

Characterization of inosine-uridine nucleoside hydrolase (RihC) from Escherichia coli
A non-specific nucleoside hydrolase from Escherichia coli (RihC) has been cloned, overexpressed, and purified to greater than 95% homogeneity. Size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis show that the protein exists as a homodimer. The enzyme showed significant activity against the standard ribonucleosides with uridine, xanthosine, and inosine having the greatest activity. The Michaelis constants were relatively constant for uridine, cytidine, inosine, adenosine, xanthosine, and ribothymidine at approximately 480 μM. No activity was exhibited against 2′-OH and 3′-OH deoxynucleosides. Nucleosides in which additional groups have been added to the exocyclic N6 amino group also exhibited no activity. Nucleosides lacking the 5′-OH group or with the 2′-OH group in the arabino configuration exhibited greatly reduced activity. Purine nucleosides and pyrimidine nucleosides in which the N7 or N3 nitrogens respectively were replaced with carbon also had no activity.
Arivett, Brock,Farone, Mary,Masiragani, Ranjith,Burden, Andrew,Judge, Shelby,Osinloye, Adedoyin,Minici, Claudia,Degano, Massimo,Robinson, Matthew,Kline, Paul
p. 656 - 662
(2014/03/21)

Meteorites as catalysts for prebiotic chemistry
From outer space: Twelve meteorite specimens, representative of their major classes, catalyse the synthesis of nucleobases, carboxylic acids, aminoacids and low-molecular-weight compounds from formamide (see figure). Different chemical pathways are identified, the yields are high for a prebiotic process and the products come in rich and composite panels.
Saladino, Raffaele,Botta, Giorgia,Delfino, Michela,Di Mauro, Ernesto
p. 16916 - 16922
(2014/01/06)

Reversal of the substrate specificity of CMP N-glycosidase to dCMP
MilB is a CMP hydrolase involved in the early steps of biosynthesis of the antifungal compound mildiomycin. An enzyme from the bacimethrin biosynthetic pathway, BcmB, is closely related to MilB in both sequence and function. These two enzymes belong to the nucleoside 2′-deoxyribosyltransferase (NDT) superfamily. NDTs catalyze N-glycosidic bond cleavage of 2′- deoxynucleosides via a covalent 2-deoxyribosyl-enzyme intermediate. Conservation of key active site residues suggests that members of the NDT superfamily share a common mechanism; however, the enzymes differ in their substrate preferences. Substrates vary in the type of nucleobase, the presence or absence of a 2′-hydroxyl group, and the presence or absence of a 5′-phosphate group. We have determined the structures of MilB and BcmB and compared them to previously determined structures of NDT superfamily members. The comparisons reveal how these enzymes differentiate between ribosyl and deoxyribosyl nucleotides or nucleosides and among different nucleobases. The 1.6 A structure of the MilB-CMP complex reveals an active site feature that is not obvious from comparisons of sequence alone. MilB and BcmB that prefer substrates containing 2′-ribosyl groups have a phenylalanine positioned in the active site, whereas NDT family members with a preference for 2′-deoxyribosyl groups have a tyrosine residue. Further studies show that the phenylalanine is critical for the specificity of MilB and BcmB toward CMP, and mutation of this phenylalanine residue to tyrosine results in a 1000-fold reversal of substrate specificity from CMP to dCMP.
Sikowitz, Megan D.,Cooper, Lisa E.,Begley, Tadhg P.,Kaminski, Pierre Alexandre,Ealick, Steven E.
p. 4037 - 4047
(2013/07/27)

Enzymatic synthesis of 2-deoxy-β-d-ribonucleosides of 8-azapurines and 8-aza-7-deazapurines
The enzymatic synthesis of 8-azapurine and 8-aza-7-deazapurine 2-deoxyribonucleosides has been studied. Two methods have been used: (i) transglycosylation employing 2-deoxyguanosine, 2-deoxycytidine, 2-deoxyuridine, and 2-deoxythymidine as 2-deoxy-d-ribofuranose donors and recombinant E. coli purine nucleoside phosphorylase (PNP) as biocatalyst, and (ii) one-pot synthesis from 2-deoxy-d-ribose and nucleobases employing recombinant E. coli ribokinase (RK), phosphopentomutase (PPM) and PNP as biocatalysts. Good substrate activity was observed for all bases studied except 2-amino-8-aza-6-chloro-7-deazapurine, which afforded the desired N9-nucleoside in moderate yield due to very low solubility of the base and partial replacement of C6-chloro atom of the base and formed nucleoside with a hydroxy group. The participation of Ser90 Oγ of E. coli PNP in the binding of 8-aza-7-deazapurines in the catalytic center of PNP followed by the formation of a productive complex and glycosidic bond is suggested. Georg Thieme Verlag Stuttgart · New York.
Stepchenko, Vladimir A.,Seela, Frank,Esipov, Roman S.,Miroshnikov, Anatoly I.,Sokolov, Yuri A.,Mikhailopulo, Igor A.
experimental part
p. 1541 - 1545
(2012/09/08)

The mitochondrial amidoxime reducing component (mARC) is involved in detoxification of N-hydroxylated base analogues
The mitochondrial Amidoxime Reducing Component (mARC) is the newly discovered fourth molybdenum enzyme in mammals. All hitherto analyzed mammals express two mARC proteins, referred to as mARC1 and mARC2. Together with their electron transport proteins cytochrome b5 and NADH cytochrome b5 reductase, they form a three-component enzyme system and catalyze the reduction of N-hydroxylated prodrugs. Here, we demonstrate the reductive detoxification of toxic and mutagenic N-hydroxylated nucleobases and their corresponding nucleosides by the mammalian mARC-containing enzyme system. The N-reductive activity was found in all tested tissues with the highest detectable conversion rates in liver, kidney, thyroid, and pancreas. According to the presumed localization, the N-reductive activity is most pronounced in enriched mitochondrial fractions. In vitro assays with the respective recombinant three-component enzyme system show that both mARC isoforms are able to reduce N-hydroxylated base analogues, with mARC1 representing the more efficient isoform. On the basis of the high specific activities with N-hydroxylated base analogues relative to other N-hydroxylated substrates, our data suggest that mARC proteins might be involved in protecting cellular DNA from misincorporation of toxic N-hydroxylated base analogues during replication by converting them to the correct purine or pyrimidine bases, respectively.
Krompholz, Nina,Krischkowski, Carmen,Reichmann, Debora,Garbe-Schoenberg, Dieter,Mendel, Ralf-R.,Bittner, Florian,Clement, Bernd,Havemeyer, Antje
p. 2443 - 2450
(2013/01/15)

Studies on the synthesis of N′-acetyl AZA-analogues of Ganciclovir - Unexpected liability of N′-(2-hydroxyethyl)-azanucleosides under basic conditions
The O′-pivaloyl diesters of N′-acetyl-azanucleosides were obtained from N-[1,3-di(pivaloyloxy)prop-2-yl]-N-(pivaloyloxymethyl)acetamide and a silylated nucleobase under Vorbruggen′s conditions. Unexpectedly, de-pivaloylation of the diesters under basic conditions afforded the corresponding nucleobase and N-acetylserinol. Mechanistic investigations showed that these products result from the following cascade of spontaneous transformations initiated by the mono de-pivaloylation of the starting diesters. N′-Deacetylation of the resultant mono-esters via the intramolecular N-O acetyl migration is the key step of the cascade; the corresponding NH-azanucleosides in the form of O-acetyl-O′-pivaloyl diesters are formed. Fragmentation of these diester intermediates gives the nucleobase and O-acetyl-O'-pivaloylserinol. Conversion of the latter to N-acetylserinol involves the selective O-N acetyl migration followed by de-pivaloylation of the resulting N-acetyl-O-pivaloylserinol. Copyright Taylor and Francis Group, LLC.
Koszytkowska-Stawinska, Mariola
experimental part
p. 768 - 785
(2011/05/04)

HUMANIZED ANTI-EGFL7 ANTIBODIES AND METHODS USING SAME
The present invention concerns antibodies to EGFL7 and the uses of same.
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(2010/12/29)

ANTIBODIES TO INSULIN-LIKE GROWTH FACTOR RECEPTOR
The invention provides various antibodies that bind to insulin-like growth factor-I receptor (IGF-1R), methods for making such antibodies, compositions and articles incorporating such antibodies, and their uses in treating, for example, cancer or aging. The antibodies include murine, chimeric, and humanized antibodies.
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(2009/04/24)

ANTIBODIES TO LYMPHOTOXIN-ALPHA
The invention provides various antibodies that bind to lymphotoxin-α, methods for making such antibodies, compositions and articles incorporating such antibodies, and their uses in treating, for example, an autoimmune disorder. The antibodies include murine, chimeric, and humanized antibodies.
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(2009/12/05)

Specific DNAS for Epigenetic Characterisation of Cells and Tissues
The present invention provides methods, nucleic acids and molecular markers for the characterization of cells, tissues and heterogeneous mixtures of cells. Specifically, it describes particular genes and genomic regions in which DNA methylation patterns are a consistent and characteristic property of different cell types, states and stages of differentiation. The invention is useful in determining the identity, composition, quality and potency of cells and cell populations. Furthermore, the invention will be useful in monitoring the differentiation of cells.
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(2009/12/24)

Antibodies and immunoconjugates and uses therefor
Anti-STEAP-1 antibodies and immunoconjugates thereof are provided. Methods of using anti-STEAP-1 antibodies and immunoconjugates thereof are provided.
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(2009/12/04)

BINDING POLYPEPTIDES WITH OPTIMIZED SCAFFOLDS
The invention provides variant heavy chain variable domains (VH) with increased folding stability. Libraries comprising a plurality of these polypeptides are also provided. In addition, compositions and methods of generating and using these polypeptides and libraries are provided.
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(2008/06/13)

Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
A novel class of compounds known as peptide nucleic acids, bind complementary DNA and RNA strands, and generally do so more strongly than the corresponding DNA or RNA strands while exhibiting increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from a group consisting of naturally-occurring nucleobases and non-naturally-occurring nucleobases, including 2,6-diaminopurine, attached to a polyamide backbone, and contain alkyl amine side chains.
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(2008/06/13)

Agents for corneal or intrastromal administration to treat or prevent disorders of the eye
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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(2008/06/13)

Peptide nucleic acids having 2,6-diaminopurine nucleobases
A novel class of compounds, known as peptide nucleic acids, bind complementary DNA and RNA strands more strongly than a corresponding DNA strand, and exhibit increased sequence specificity and binding affinity. The peptide nucleic acids of the invention comprise ligands selected from a group consisting of naturally-occurring nucleobases and non-naturally-occurring nucleobases attached to a polyamide backbone. Some PNAs of the invention also contain C1-C8alkylamine side chains.
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(2008/06/13)

A solid-state 17O nuclear magnetic resonance study of nucleic acid bases
We report a systematic solid-state 17O NMR study of free nucleic acid bases: thymine (T), uracil (U), cytosine (C), and guanine (G). Site-specifically 17O-enriched samples were synthesized: [2-17O]thymine (1), [4-17O]thymine (2), [2-17O]uracil (3), [4-17O]uracil (4), [2-17O]cytosine (5), and [6-17O]guanine monohydrate (6). Magic-angle-spinning (MAS) and static 17O NMR spectra were acquired at 11.75 T for compounds 1-6, from which information about the 170 chemical shift and electric field gradient tensors was obtained. Extensive quantum chemical calculations were performed at the B3LYP/6-311++G(d,p) level of theory for 17O NMR properties in various molecular models. The calculated 17O NMR tensors are highly sensitive to the description of intermolecular hydrogen-bonding interactions at the target oxygen atom. A reasonably good agreement between experimental solid-state 17O NMR data and B3LYP/6-311++G(d,p) calculations is achievable only in molecular cluster models where a complete hydrogen-bond network is considered. Using this theoretical approach, we also investigated the 17O NMR tensors in two unusual structures: guanine- and uracil-quartets.
Wu, Gang,Dong, Shuan,Ida, Ramsey,Reen, Nitin
p. 1768 - 1777
(2007/10/03)

Labeled nucleosides and method for their preparation
The invention relates to a method for the chemical preparation of labeled nucleosides via an oxidative-ring-opening step and a reductive-ring-closure step starting from a labeled D-glucose nucleoside resulting in the corresponding D-ribose-nucleoside by removing the carbon atom 3 on the glucose and comprising the steps of:1. a protection of the sugar ring hydroxyl groups,2. a sugar-base condensation, whereby the base is a purine or a pyrimidine,3. a deprotection of the sugar ring hydroxyl groups,4. an oxidative-ring-opening and removal of the carbon atom 3, and5. a reductive-ring-closure resulting in labeled D-ribose-nucleoside.The invention further relates to a compound obtainable via the method according to the invention having the formula selected from [13C,15N] labeled 6'-O-mono- or 6'-O-bis-C1-C6-alkyloxytrityl-D-glycopyranosyl nucleosides, or [13C,15N] labeled tetra-O-acetyl-D-glycopyranosyl nucleosides or [13C,15N] labeled glycopyranosyl nucleosides.
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(2008/06/13)

A possible prebiotic synthesis of purine, adenine, cytosine, and 4(3H)-pyrimidinone from formamide: Implications for the origin of life
The synthesis of prebiotic molecules is a major problem in chemical evolution as well as in any origin-of-life theory. We report here a plausible new prebiotic synthesis of naturally occurring purine and pyrimidine derivatives from formamide under catalytic conditions. In the presence of CaCO3 and different inorganic oxides, namely silica, alumine, kaolin, and zeolite (Y type), neat formamide undergoes the formation of purine, adenine, cytosine, and 4(3H)-pyrimidinone, from acceptable to good yields. The role of catalysts showed to be not limited to the improvement of the yield but it is also relevant in providing a high selectivity in the products distribution.
Saladino, Raffaele,Crestini, Claudia,Costanzo, Giovanna,Negri, Rodolfo,Di Mauro, Ernesto
p. 1249 - 1253
(2007/10/03)

Composition of matter having bioactive properties
Particles of coordinated complex comprising a basic, hydrous polymer and a capacitance adding compound, as well as methods for their production, are described. These complexes exhibit a high degree of bioactivity making them suitable for a broad range of applications through their incorporation into conventional vehicles benefiting from antimicrobial and similar properties.
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(2008/06/13)

Investigation of the kinetics of degradation of hexopyranosylated cytosine nucleosides using liquid chromatography
Liquid chromatography was used to follow the degradation of hexopyranosylated cytosine nucleosides in buffers of acid, neutral and alkaline pH and of constant ionic strength. The compounds were found to degrade by hydrolysis to cytosine and/or by deamination to the corresponding uracil nucleosides. Degradation in acid is influenced by the number of sugar hydroxyl groups, presence of sugar double bonds and the type of anomer. Stability of some of the compounds was compared with that of related thymine nucleosides. Temperature studies support a unimolecular mechanism of hydrolysis at pH 1.22.
Thoithi, Grace N.,Van Schepdael, Ann,Busson, Roger,Janssen, Gerard,Van Aerschot, Arthur,Herdewijn, Piet,Roets, Eugene,Hoogmartens, Jos
p. 189 - 203
(2007/10/03)

Photochemical reactions of 5-fluoropyrimidine bases with alcohols
Photochemical reactions of 5-fluorocytosine with primary alcohols led to 5-alkoxycytosines and 6-alkoxycytosines as the main photoproducts. These products are formed via reactive intermediates 6-alkoxy-5-fluoro-5,6- dihydrocytosines, whereas photochemical reactions of 5-fluorouracil with alcohols led to stable 6-alkoxy-5-fluoro-5,6-dihydrouracils.
Urjasz, Wojciech,Maciejewski, Andrzej,Celewicz, Lech
p. 3243 - 3246
(2007/10/03)

Antisense oligomers
Antisense oligomers of the formula STR1 wherein R1, R2 and R4 are independently hydrogen, lower alkyl or acyl; R3 is hydrogen or lower alkyl; B is a nucleobase or a protected nucleobase, such that said oligomer has a sequence of bases complementary to a selected RNA; n is 5 to 30; X is NR3 R4 ; Y is OR3, or NHR3 ; as well as, pharmaceutically acceptable salts thereof.
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(2008/06/13)

Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
A novel class of compounds, known as peptide nucleic acids, bind complementary DNA and RNA strands more strongly than a corresponding DNA strand, and exhibit increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from a group consisting of naturally-occurring nucleobases and non-naturally-occurring nucleobases attached to a polyamide backbone, and contain C1 -C8 alkylamine side chains. Methods of enhancing the solubility, binding affinity and sequence specificity of PNAs are provided.
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(2008/06/13)

Peptide nucleic acids having amino acid side chains
A novel class of compounds, known as peptide nucleic acids, bind complementary DNA and RNA strands more strongly than the corresponding DNA or RNA strands, and exhibit increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from a group consisting of naturally-occurring nucleobases and non-naturally-occurring nucleobases attached to a polyamide backbone, and contain alkylamine side chains.
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(2008/06/13)

Synthesis of dihydroisoxazole nucleoside and nucleotide analogs
The dihydroisoxazole nucleosides as well as their phosphonate derivatives were efficiently prepared via 1,3-dipolar cycloaddition reactions of nitrile oxides with corresponding vinyl nucleoside bases for antiviral studies.
Gi, Hung-Jang,Xiang, Yuejun,Schinazi, Raymond F.,Zhao, Kang
p. 88 - 92
(2007/10/03)

N3-alkyl-2',5'-0-silylated-3'-spiro-thymidine derivatives
Nucleoside analogs possessing anti-HIV activity and having a 3'-spiro moiety and blocking groups at the 2'- and 5'-positions. The preferred species is shown in the structure below: STR1 wherein R is alkyl.
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(2008/06/13)

Photochemical deamination and demethylation of 5-methylcytosine
Cytosine methylation is believed to play a pivotal role in eucaryotic cellular development as well as in viral latency. We have been investigating chemical mechanisms for the perturbation of methylation patterns, including the effects of ultraviolet radiation. We observed that, upon exposure to UV light, 5-methylcytosine (5mC) was converted to thymine, cytosine, and a series of 5-substituted cytosine derivatives as analyzed by gas chromatography/mass spectrometry. Deamination of 5mC to thymine proceeds via formation of the intermediate photohydrate. Formation of 5-substituted cytosine derivatives results from oxidation of the 5-methyl group with initial formation of 5-(hydroxymethyl)cytosine (hmC). Upon exposure to UV light, hmC is converted to cytosine. The conversion of hmC to cytosine likely results from photohydration and elimination of formaldehyde. It is proposed that endogenous oxidation and hydrolysis could result in demethylation of 5mC residues in DNA. Whereas hydrolytic deamination of 5mC to thymine has been widely discussed, demethylation of 5mC has not as yet been described.
Privat, Eric,Sowers, Lawrence C.
p. 745 - 750
(2007/10/03)

Oligoribonucleotides with amide backbone
Oligomers having amide linkages of the following formula: ???wherein R1 is H, C1 4 alkyl, C1 18-acyl or hydroxy-lower alkyl; R2 is H, aralkyl, or C1 4 alkyl; B is a nucleoside base residue selected from the group consisting of adenine, cytosine, guanine, thymine, uracil; X is H, OR1, NHR2 or NH-acyl; Y is OR2 or NHR2; and n is a number from 5 through 25, and salts thereof.
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(2008/06/13)