- Syntheses of 2-amino-4,6-dichloro-5-nitropyrimidine and 2-amino-4,5,6-trichloropyrimidine: an unusual aromatic substitution
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2-Amino-4,6-dichloro-5-nitropyrimidine is an intermediate required for the preparation of nitropyrimidines as inactivators of the DNA repairing protein MGMT. When attempting its synthesis, 2-amino-4,5,6-trichloropyrimidine is obtained instead, via unusual aromatic substitution of the nitro group in 2-amino-4-hydroxy-5-nitropyrimidin-6-one by chloride. The synthesis, the reactivity of 4,5,6-trichloropyrimidine and the efficient preparation of 2-amino-4,6-dichloro-5-nitropyrimidine are presented.
- Lopez, Sergio,McCabe, Thomas,Stanley McElhinney,McMurry, T. Brian H.,Rozas, Isabel
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- Synthesis and structure-activity relationships of guanine analogues as phosphodiesterase 7 (PDE7) inhibitors
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The synthesis of a novel series of guanine analogues is reported. The compounds have been assessed in vitro and some analogues have been found to be inhibitors of phosphodiesterase type 7 (PDE7).
- Barnes, Matthew J,Cooper, Nicola,Davenport, Richard J,Dyke, Hazel J,Galleway, Fiona P,Galvin, Frances C.A,Gowers, Lewis,Haughan, Alan F,Lowe, Christopher,Meissner, Johannes W.G,Montana, John G,Morgan, Trevor,Picken,Watson, Robert J
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- Diaminomethyleneaminocarbonyldinitromethane, formed during the preparation of 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone by nitration of 2-amino-6-chloro-4(3H)-pyrimidinone
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Difficulties in the nitration of 2-amino-6-chloro-4(3H)-pyrimidinone to give the widely used heterocyclic precursor 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone are shown to be due to formation of an unusual open-chain gem-dinitro compound, identified as diaminomethyleneaminocarbonyldinitromethane. The latter is also formed by the nitration of 2-amino-4,6(3H,5H)-pyrimidinedione. It decomposes with loss of carbon dioxide in dimethyl sulfoxide, or in aqueous potassium hydroxide, to give guanidine and dinitromethane.
- Boyle, Peter H.,Daly, Karen M.,Leurquin, Fabien,Robinson, J. Kenneth,Scully, Damien T.
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- SOLID-PHASE SYNTHESIS OF OLIGONUCLEOTIDES CONTAINING N6-(2-DEOXY-ALPHA,BETA-DERYTHROPENTOFURANOSYL)-2,6-DIAMINO-4-HYDROXY-5-FORMAMIDOPYRIMIDINE (Fapy.dG)
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A strategy using reverse phosphoramidites for synthesizing oligonucleotides containing Fapy.dG is disclosed.
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Paragraph 0093-0094
(2021/08/06)
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- Synthesis of Oligonucleotides Containing the N6-(2-Deoxy-α,β-d-erythropentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy?dG) Oxidative Damage Product Derived from 2′-Deoxyguanosine
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N6-(2-Deoxy-α,β-d-erythropentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy?dG) is a major DNA lesion produced from 2′-deoxyguanosine under oxidizing conditions. Fapy?dG is produced from a common intermediate that leads to 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-OxodGuo), and in greater quantities in cells. The impact of Fapy?dG on DNA structure and function is much less well understood than that of 8-OxodGuo. This is largely due to the significantly greater difficulty in synthesizing oligonucleotides containing Fapy?dG than 8-OxodGuo. We describe a synthetic approach for preparing oligonucleotides containing Fapy?dG that will facilitate intensive studies of this lesion in DNA. A variety of oligonucleotides as long as 30 nucleotides are synthesized. We anticipate that the chemistry described herein will provide an impetus for a wide range of studies involving Fapy?dG.
- Greenberg, Marc M.,Tang, Joel A.,Yang, Haozhe
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supporting information
(2020/04/23)
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- Microwave-assisted synthesis and docking studies of phenylureas as candidates for the drug design against the biological warfare agent Yersinia pestis
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Background: Bubonic plague is amongst the diseases with the highest potential for being used in biological warfare attacks today. Introduction: This disease, caused by the bacterium Yersina pestis, is highly infectious and can achieve 100% of fatal victims when in its most dangerous form. Besides, there is no effective vac-cine, and the chemotherapy available today against plague is ineffective if not administered at the beginning of the infection. Willing to contribute for changing this reality we propose here new phe-nylureas as candidates for the drug design against plague meant to target the enzyme dihydrofolate reductase from Y. pestis (YpDHFR). Methods: Seven phenylureas, four of them new, were synthesized, following synthetic routes adapted from procedures available in the literature, and using microwave irradiation. After, they were submitted to docking studies inside YpDHFR and human DHFR (HssDHFR) in order to check their potential as selective inhibitors. Results & Conclusion: Our results revealed four new phenylureas and a new synthetic route for this kind of molecule using microwave irradiation. Also, our docking studies pointed to two of the phe-nylureas as selective inhibitors of YpDHFR and, therefore, candidates for the design of new drugs against plague.
- Bastos, Leonardo da Costa,Bendahan, David,Chacón-Huete, Franklin,Cuya, Teobaldo,Forgione, Pat,Fran?a, Tanos Celmar Costa,Sirouspour, Mehdi
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p. 631 - 637
(2020/04/17)
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- BIOACTIVE COMPOUNDS FOR TREATMENT OF CANCER AND NEURODEGENERATIVE DISEASES
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The invention provides bioactive compounds for the treatment of various malconditions such as cancer and neurodegenerative diseases including Alzheimer's disease. The chemical compounds as disclosed herein are found to show bioactivity in bioassays related to these conditions. Pharmaceutical compositions, combinations and methods of synthesis are provided, as are methods of using the compound, compositions and combinations in the treatment of the diseases.
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Page/Page column 93-94
(2009/12/23)
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- TRIAZOLO [4, 5-D] PYRAMIDINE DERIVATIVES AND THEIR USE AS PURINE RECEPTOR ANTAGONISTS
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Compounds of formula (I) that are capable of acting as purine receptor antagonists, pharmaceutical compositions including the compounds, and methods of making the compounds, are. disclosed. The compounds and compositions can be used in treating or preventing disorders related to purine receptor hyperfunctioning.
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Page/Page column 27-28
(2010/01/30)
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- Synthesis and antimicrobial evaluation of guanylsulfonamides
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A series of guanylsulfonamides, 2-amino-9-[2-substituted-4-(4-substituted piperidin-1-sulfonyl)phenyl]-1,9-dihydropurin-6-ones, was synthesized by adopting reductive aminoformylation of 2-amino-5-nitro-6-[4-(piperidin-1-sulfonyl)phenylamino]-3H-pyrimidin- 4-one and subsequent intramolecular ring condensation as key steps. All the guanylsulfonamides were assayed for their in vitro antibacterial activities against Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Streptococcus faecalis, and their antifungal activities against Aspergillus flavus, Aspergillus niger, and Candida albicans. Of the guanylsulfonamides, 13e and 13f displayed better antibacterial activities than that of Norfloxacin against the bacterial strains S. aureus and S. faecalis except 13f against S. faecalis, which exhibited the activity similar to that of Norfloxacin. Against the fungal strains A. flavus and A. niger, 13g and 13h showed similar activities to that of Griseoflavin-16 except 13h against A. niger, which displayed a profound drop in the activity compared to that of Griseoflavin-16. The remarkable inhibition of the growth of the bacterial and fungal strains makes these substances promising microbial agents.
- Patel, Pratik R.,Ramalingan, Chennan,Park, Yong-Tae
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p. 6610 - 6614
(2008/09/18)
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- Synthesis of oligonucleotides containing Fapy·dG (N 6-(2-deoxy-α,β-D-erythropentofuranosyl)-2, 6-diamino-4-hydroxy-5-formamidopyrimidine) using a 5′-dimethoxytrityl dinucleotide phosphoramidite
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(Chemical Equation Presented). Fapy·dG (N6-(2-deoxy- α,β-D-erythropentofuranosyl)-2,6-diamino-4-hydroxy-5- formamidopyrimidine) is a modified purine lesion produced by a variety of DNA-damaging agents, which shows interesting biochemical proper
- Yu, Lin Jiang,Wiederholt, Carissa J.,Patro, Jennifer N.,Haraguchi, Kazuhiro,Greenberg, Marc M.
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p. 141 - 149
(2007/10/03)
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- Synthesis, stability, and conformation of the formamidopyrimidine G DNA lesion.
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The formamidopyrimidine (FapydGua) lesion, derived from the nucleobase guanine, is a major DNA lesion involved in mutagenesis and carcinogenesis. To date, the chemical information available about this main lesion is very limited. Herein, we describe a synthesis and a detailed characterization of the acetyl-protected monomer of the FapydGua lesion. Stability studies in DMSO and in water/acetonitrile show that the N-glycosidic bond, previously thought to be highly labile, is much more stable than anticipated. Decomposition of the FapydGua lesion proceeds with half-life times of 37.8 h for the beta-anomer and 65.2 h for the alpha-anomer in water/acetonitrile. The relaxation time for the anomerization reaction was determined to tau = 6.5 h at room temperature. Most important, it was found that the formamido group, which is critical for the lesion recognition process by repair enzymes, is fixed in the cis-conformation in apolar solvents such as chloroform. This conformation enables the formation of a hydrogen bond between the carbonyl oxygen of the formamide and the NH of the N-glycosidic bond within the framework of a seven-membered ring system. This has consequences for the recognition of the lesion by repair enzymes (hOGG1 and Fpg protein). These enzymes were so far believed to recognize the carbonyl group of the FapydGua lesion. Our investigations show that this carbonyl group is not readily accessible because it is almost buried in the dominating cis-conformation. In agreement with the recent X-ray structure of hOGG1 in complex with 8-oxo-7,8-dihydroguanine-containing DNA, we can conclude that repair enzymes can contact both lesions only via the N(7)-H group, which is a hydrogen-bond acceptor in guanine.
- Burgdorf, Lars T,Carell, Thomas
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p. 293 - 301
(2007/10/03)
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- Adenosine receptor ligands and their use in the treatment of disease
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The invention relates to cyclic heteroaromatic compounds, containing at least one nitrogen atom, and to their use in the manufacture of medicaments for the treatment of diseases, related to adenosine receptor modulators, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure, substance abuse, sedation and they may be active as muscle relaxants, antipsychotics, anti epileptics, anticonvulsants and cardiaprotective agents.
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- The chemical development of CI-972 and CI-1000: A continuous nitration, a MgCl2/Et3N-mediated C-alkylation of a chloronitropyrimidine, a catalytic protodediazotizatlon of a diazonium salt, and an air oxidation of an amine
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Efficient, large-scale processes were developed for the preparation of the potent PNP inhibitors 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride, monohydrate (1) and 2-amino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride, monohydrate (2). We report (1) a safe, continuous nitration process for the preparation of 2-amino-6-chloro-5-nitro-4-pyrimidinol (8a) and its stable diisopropylamine salt (8b), (2) the first MgCl2/ Et3N-mediated C-alkylation of a chloronitropyrimidine, (3) a rare catalytic protodediazotization of the diazonium salt 2-amino-4-oxo-7-thiophen-3-ylmethyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6- diazonium chloride (14), (4) a single-step process to prepare 2 directly from 2-amino-6-hydroxy-5-nitro-a-(3-thienylmethyl)-4-pyrimidineacetonitrile (12) using a sponge nickel-catalyzed reduction, and (5) a method to convert the over-reduction by-product 2,5-diamino-6-(1-aminomethyl-2-thiophen-3-yl-ethyl)-pyrimidin-4-ol (16) into 2 using air oxidation.
- De Jong, Randall L.,Davidson, James G.,Dozeman, Gary J.,Fiore, Philip J.,Giri, Punam,Kelly, Margaret E.,Puls, Timothy P.,Seamans, Ronald E.
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p. 216 - 225
(2013/09/07)
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- Novel intermediates for the preparation of Carbovir
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The invention provides novel cyclopentenyl carbinol compounds which are useful as intermediates for the preparation of the anti-AIDS drug, Carbovir. Processes for the preparation of such novel compounds and for the use of the compounds to make Carbovir are also provided.
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- Specific Inhibitors in Vitamin Biosynthesis. Part 7. Syntheses of Blocked 7,8-Dihydropteridines via &α-Amino Ketones
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The synthesis of 15 blocked 7,8-dihydropteridines is described in which the pyrazine ring is built from a derivative of an α-amino ketone.Three routes to the amino ketones based upon amino acids, nitrosyl chloride addition to alkenes, and nitro alcohols are discussed.The compounds synthesised are inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase , an enzyme in the pathway leading to dihydrofolate, and the inhibitory potencies of the compounds are discussed in the light of a hypothetical active site model for the enzyme.
- Al-Hassan, Saiba S.,Cameron, Robert J.,Curran, Adrian W. C.,Lyall, William J. S.,Nicholson, Sydney H.,et al.
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p. 1645 - 1660
(2007/10/02)
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- Method of synthesis of pteridines
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A pharmaceutical formulation of a compound of formula (II') SPC1 wherein Y is a lower alkyl group, in association with a pharmaceutically acceptable carrier, as an antibacterial product, and methods involving the preparation and reductive cyclization of a compound of formula (IV) SPC2 wherein X is a lower alkyl group or a hydroxymethyl group.
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