- Design and synthesis of purine analogues as highly specific ligands for FcyB, a ubiquitous fungal nucleobase transporter
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In the course of our study on fungal purine transporters, a number of new 3-deazapurine analogues have been rationally designed, based on the interaction of purine substrates with the Aspergillus nidulans FcyB carrier, and synthesized following an effective synthetic procedure. Certain derivatives have been found to specifically inhibit FcyB-mediated [3H]-adenine uptake. Molecular simulations have been performed, suggesting that all active compounds interact with FcyB through the formation of hydrogen bonds with Asn163, while the insertion of hydrophobic fragments at position 9 and N6 of 3-deazaadenine enhanced the inhibition.
- Lougiakis, Nikolaos,Gavriil, Efthymios-Spyridon,Kairis, Markelos,Sioupouli, Georgia,Lambrinidis, George,Benaki, Dimitra,Krypotou, Emilia,Mikros, Emmanuel,Marakos, Panagiotis,Pouli, Nicole,Diallinas, George
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Read Online
- Structure-based design, synthesis, and antimicrobial activity of purine derived SAH/MTA nucleosidase inhibitors
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The structure-based design, synthesis, and biological activity of novel inhibitors of S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Using 6-substituted purine and deaza purines as the core scaffolds, a systematic and structure guided series of modifications provided low nM inhibitors with broad-spectrum antimicrobial activity.
- Tedder, Martina E.,Nie, Zhe,Margosiak, Stephen,Chu, Shaosong,Feher, Victoria A.,Almassy, Robert,Appelt, Krzysztof,Yager, Kraig M.
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Read Online
- N6-isopentenyladenosine a new potential anti-angiogenic compound that targets human microvascular endothelial cells in vitro
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N6-isopentenyladenosine is an anti-proliferative and pro-apoptotic atypical nucleoside for normal and tumor cells. Considering the role of angiogenesis in various diseases, we investigated the cytotoxic effect of N6-isopentenyladenosine on human microvascular endothelial cells, protagonists in angiogenesis. Our results show that N6-isopentenyladenosine induced a significant reduction of cell viability, upregulated p21 and promoted caspase-3 cleavage in a dose dependent manner leading to apoptotic cell death as detected by FACS analysis. To understand structure-function relationship of N6-isopentenyladenosine, we investigated the effect of some N6-isopentenyladenosine analogs. Our results suggest that N6-isopentenyladenosine and some of its derivatives are potentially novel angiostatic agents and might be associated with other anti-angiogenic compounds for a better outcome.
- Castiglioni, Sara,Romeo, Valentina,Casati, Silvana,Ottria, Roberta,Perrotta, Cristiana,Ciuffreda, Pierangela,Maier, Jeanette A. M.
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Read Online
- Mechanism of formation of N2-benzylguanine in the reaction of 2-amino- 6-chloropurine with sodium benzyl oxide, and benzylation of nucleic acid bases
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The mechanism of formation of N2-benzylguanine in the reaction of 2- amino-6-chloropurine with a large excess (12-13 molar eq) of sodium benzyl oxide in benzyl alcohol at 130°C was studied. N2,O6-Dibenzylguanine, a reaction intermediate, was isolated and a possible mechanism for its formation is discussed. Furthermore, using this sodium benzyl oxide system, benzylation at the amino group of nucleic acid bases was facilitated.
- Koyama, Ken-Ichi,Hitomi, Kenichi,Terashima, Isamu,Kohda, Kohfuku
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Read Online
- Reactions of Adenine and Its N-Exo Substituted Analogues with Phenyl Glycidyl Ether
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Abstract: The features of reactions of adenine with phenyl glycidyl ether depending on the solvent nature were studied. In DMF in the presence of K2CO3, an N9-alkyl derivative, an experimental antiviral drug 9-(2-hydroxy-3-phenoxypropyl)adenine, was formed predominantly. During alkylation in acetic acid, besides N9-, N3-, and N7-alkylation products were also isolated. Alkylation of 6-[alkyl(dialkyl)amino]purines with phenyl glycidyl ether in DMF produced N-exo substituted 9-(2-hydroxy-3-phenoxypropyl)adenine analogues.
- Neporozhneva,Studentzsov,Ramsh
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p. 2248 - 2254
(2021/02/12)
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- Efficient Phosphorus-Free Chlorination of Hydroxy Aza-Arenes and Their Application in One-Pot Pharmaceutical Synthesis
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The chlorination of hydroxy aza-arenes with bis(trichloromethyl) carbonate (BTC) and SOCl2 has been effectively performed by refluxing with 5 wt % 4-dimethylaminopyridine (DMAP) as a catalyst. Various substrates are chlorinated with high yields. The obtained chlorinated aza-arenes can be used directly with simple workup for succedent one-pot synthesis on a large scale.
- Wang, Jian,Li, Yan-Hui,Pan, Song-Cheng,Li, Ming-Fang,Du, Wenting,Yin, Hong,Li, Jing-Hua
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p. 146 - 153
(2020/03/10)
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- Chemoenzymatic synthesis of cytokinins from nucleosides: Ribose as a blocking group
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Nucleoside phosphorylases are involved in the salvage pathways of nucleoside biosynthesis and catalyze the reversible reaction of a nucleobase with α-d-ribose-1-phosphate to yield a corresponding nucleoside and an inorganic phosphate. The equilibrium of these reactions is shifted towards nucleosides, especially in the case of purines. Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is widely used in labs and industry for the synthesis of nucleosides of practical importance. Bacterial PNPs have relatively broad substrate specificity utilizing a wide range of purines with different substituents to form the corresponding nucleosides. To shift the reaction in the opposite direction we have used arsenolysis instead of phosphorolysis. This reaction is irreversible due to the hydrolysis of the resulting α-d-ribose-1-arsenate. As a result, heterocyclic bases are formed in quantitative yields and can be easily isolated. We have developed a novel method for the preparation of cytokinins based on the enzymatic cleavage of the N-glycosidic bond of N6-substituted adenosines in the presence of PNP and Na2HAsO4. According to the HPLC analysis the conversion proceeds in quantitative yields. In the proposed strategy the ribose residue acts as a protective group. No contamination of the final products with AsO43- has been detected via HPLC-HRMS; simple analytical arsenate detection via ESI-MS has been proposed.
- Oslovsky, Vladimir E.,Solyev, Pavel N.,Polyakov, Konstantin M.,Alexeev, Cyril S.,Mikhailov, Sergey N.
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p. 2156 - 2163
(2018/03/26)
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- 6-benayl aminopurine synthetic method
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The invention discloses a 6-benayl aminopurine synthetic method. The method takes hypoxanthine as a raw material, thionyl chloride is taken as a solvent, phosgene or diphosgene or triphosgene is takenas a chloride agent, 4-dimethylaminopyridine or dialkyl aminopyridine is taken as a catalyst for a reaction, after the reaction is completed, 6-chloropurine is obtained, distilled thionyl chloride and phosgene dissolved in thionyl chloride are completely used for a next reaction, and then the obtained 6-chloropurine and benzylamine are subjected to the reaction to synthesize 6-benayl aminopurineunder existence of triethylamine. During a reaction process, the used chloride agent solid triphosgene is completely decomposed to the phosgene dissolved in the solvent under existence of the catalyst4-dimethylaminopyridine, and no solid constituent is residual.
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Paragraph 0020; 0021
(2018/07/30)
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- Preparation method of 6-benzylaminopurine
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The invention relates to a preparation method of 6-benzylaminopurine and belongs to the technical field of pesticide synthesis. Aiming at solving the problems that an existing reaction route is long and the quality is poor, the invention provides the preparation method of the 6-benzylaminopurine. The method comprises the following steps: in the presence of a compound catalyst of I2, P2O5 and ZnCl2, enabling hypoxanthine and benzylamine to react in an N,N-dimethylformamide solvent under the condition that the temperature is 50 DEG C to 75 DEG C; regulating the pH (Potential of Hydrogen) value to be neutral to obtain a product, wherein the mass ratio of the hypoxanthine to the compound catalyst is 1 to (0.3 to 0.5); the mass ratio of the P2O5 to the ZnCl2 to the I2 is 1 to (0.2 to 0.3) to (0.01 to 0.02). According to the preparation method provided by the invention, a DMF (Dimethyl Formamide)-P2O5-ZnCl2-I2 compound catalysis system can be formed and has a synergistic effect to finish a one-step method; the preparation method has the advantage that the reaction route is short and can also have the effect of relatively high yield and product purity.
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Paragraph 0021; 0023; 0025; 0028; 0031; 0034; 0037
(2018/03/24)
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- New tools in nucleoside toolbox of tick-borne encephalitis virus reproduction inhibitors
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Design and development of nucleoside analogs is an established strategy in the antiviral drug discovery field. Nevertheless, for many viruses the coverage of structure-activity relationships (SAR) in the nucleoside chemical space is not sufficient. Here we present the nucleoside SAR exploration for tick-borne encephalitis virus (TBEV), a member of Flavivirus genus. Promising antiviral activity may be achieved by introduction of large hydrophobic substituents in the position 6 of adenosine or bulky silyl groups to the position 5′. Introduction of methyls to the ribose moiety does not lead to inhibition of TBEV reproduction. Possible mechanisms of action of these nucleosides include the inhibition of viral entry or interaction with TBEV non-structural protein 5 methyltransferase or RNA-dependent RNA polymerase domains.
- Orlov, Alexey A.,Drenichev, Mikhail S.,Oslovsky, Vladimir E.,Kurochkin, Nikolay N.,Solyev, Pavel N.,Kozlovskaya, Liubov I.,Palyulin, Vladimir A.,Karganova, Galina G.,Mikhailov, Sergey N.,Osolodkin, Dmitry I.
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supporting information
p. 1267 - 1273
(2017/06/19)
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- Method for synthesizing adenine and derivatives thereof
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The invention discloses a method for synthesizing adenine and derivatives thereof. The method comprises the steps: firstly, subjecting diethyl malonate and dimethyl dioxirane to an oxidation reaction, so as to obtain 2-hydroxyldiethyl malonate; then, carrying out an ammonolysis reaction with ammonia water, so as to obtain 2-hydroxyl malonamide; then, carrying out a cyclization reaction with trimethyl orthoformate, so as to obtain 5-hydroxyl pyrimid-4,6-(1H,5H)-dione; then, carrying out a chlorination reaction with phosgene, so as to obtain 4,5,6-trichloropyrimidine; then, carrying out a cyclization reaction with formamidine hydrochloride, so as to obtain 4-chloro-1H-pyrazol[3, 4-d]pyrimidine; finally, carrying out an ammoniation reaction with ammonia water or an amine compound in the presence of triethylamine, thereby obtaining the adenine and derivatives thereof. According to the method, the raw materials are moderately-priced and readily available, the reaction conditions are mild, the reaction process is safe, the requirements on production equipment are low, particularly, the environmental pollution is light, and the yield is relatively high, so that the method is applicable to industrial large-scale production.
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Paragraph 0051; 0052
(2017/07/19)
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- IMAGING AGENTS FOR NEURAL FLUX
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Provided herein are radiolabeled compounds useful for non-invasive imaging techniques. An exemplary radiolabeled compound provided herein is useful as a radiotracer for positron emission tomography. The present application also provides unlabeled compounds useful in methods of treating diseases of the central nervous system or disease of the peripheral nervous system. Methods for preparing radiolabeled compounds, preparing unlabeled compounds, and diagnostic methods using labeled or unlabeled compounds are also provided.
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Page/Page column 125; 126
(2016/02/10)
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- Selective and recyclable rhodium nanocatalysts for the reductive N-alkylation of nitrobenzenes and amines with aldehydes
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Rhodium nanocatalysts were prepared and applied for the reductive N-alkylation of nitrobenzenes and amines to the corresponding secondary amines with aldehydes and ketones. Functional nitrobenzenes, such as nitrobenzenes with F, Cl, Br, CH3O and CH3 were transformed to the corresponding secondary amines in good to excellent yields. Moreover, the Rh@CN catalyzed N-alkylation of a series of primary amines with aldehydes and ketones also gave the corresponding secondary amines in high yields. The Rh@CN is heterogeneous, and can be reusable several times (at least 4 times) for the reductive N-alkylation of nitroarenes.
- Huang, Lei,Wang, Zhi,Geng, Longfei,Chen, Rizhi,Xing, Weihong,Wang, Yong,Huang, Jun
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p. 56936 - 56941
(2015/07/15)
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- Lewis acid-catalyzed generation of C-C and C-N bonds on π-deficient heterocyclic substrates
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Focused microwave irradiation of a series of halogenated nitrogen heterocycles and different kinds of nucleophiles in the presence of a catalytic amount of indium trichloride leads to the efficient and completely regioselective generation of aromatic C-C and C-N bonds. The method is simple, rapid, general and inexpensive, and can be performed without the use of dried solvents. Most of the synthetized compounds are new and in many cases the work-up required only filtration. Furthermore, this is the first example of the use of a Lewis acid as a catalyst for heteroarylation, vinylation and amination reactions on π-deficient heterocyclic substrates.
- Staderini, Matteo,Bolognesi, Maria Laura,Menndez, J. Carlos
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supporting information
p. 185 - 195
(2015/01/30)
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- Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors
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A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency.
- Burdick, Daniel J.,Wang, Shumei,Heise, Christopher,Pan, Borlan,Drummond, Jake,Yin, Jianping,Goeser, Lauren,Magnuson, Steven,Blaney, Jeff,Moffat, John,Wang, Weiru,Chen, Huifen
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supporting information
p. 4728 - 4732
(2015/10/28)
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- Method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK)
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The present invention relates to a method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) and the use of the compounds in the prevention or treatment of disease, including pre-diabetes, type 2 diabetes, syndrome X, metabolic syndrome and obesity.
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Paragraph 0051-0052
(2014/10/16)
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- Convenient and efficient syntheses of N6-and N 4-substituted adenines and cytosines and their 2-deoxyribosides
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Convenient and efficient methods of the synthesis of N6-and N4-substituted derivatives of adenine and cytosine and their 2-deoxyribosides were developed. The reactions of either unprotected nucleobases (adenine, cytosine) or unprotected 2-deoxyribosides with aryl or alkyl aldehydes give corresponding Schiff bases that can be reduced to the target title compounds with high overall yields. In the case of aryl aldehydes the imine derivatives are obtained in the presence of methoxides in methanol and reduced with sodium borohydride. The corresponding reactions with alkyl aldehydes require the use of acetic acid and borane dimethyl sulfide complex instead.
- Adamska, Ewelina,Barciszewski, Jan,Markiewicz, Wojciech T.
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p. 861 - 871
(2013/02/23)
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- N6-acetyl-2,3,5-tri-O-acetyladenosine; A convenient, missed out substrate for regioselective N6-alkylations
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A simple and efficient route to N6-acetyl-2,3,5-tri-O- acetyladenosine (1) was developed based on selective N-deacetylation of pentaacetylated adenosine 2 with methanol at room temperature in the presence of imidazole. Preparative synthesis of 1 was elaborated utilizing a crude mixture of 2 and 1 which is produced by reaction of adenosine with acetic anhydride in pyridine at elevated temperatures. The total yield of 1 was 80-85% starting with adenosine. It was shown that 1 is a convenient substrate for selective N 6-alkylations. The study revealed the same regioselectivity in base-promoted reactions of 1 with activated alkyl halides and Mitsunobu reactions of 1 with alcohols. A series of N6-alkyladenosines 5a-f were prepared. Cytokinins 6b,d,e were prepared by enzymatic transformation of parent nucleoside derivatives 5b,d,e using a combination of nucleoside phosphorylase and alkaline phosphatase. Georg Thieme Verlag Stuttgart, New York.
- Tararov, Vitali I.,Kolyachkina, Svetlana V.,Alexeev, Cyril S.,Mikhailov, Sergey N.
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experimental part
p. 2483 - 2489
(2011/09/20)
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- Regioselective alkylation of the exocyclic nitrogen of adenine and adenosine by the Mitsunobu reaction
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A novel synthetic route to N6-substitution of adenine is presented, employing the Mitsunobu reaction as the key step. A range of primary and secondary alcohols all coupled in very good to excellent yields within 30 min at 45 °C, offering a milder alternative to the traditional nucleophilic aromatic substitution of 6-chloropurine. The utility of this protocol is further demonstrated by its application to the syntheses of N6,N9-di-substituted adenines, including the potent and selective A1 adenosine receptor agonist N6-cyclopentyladenosine.
- Fletcher, Steven
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experimental part
p. 2948 - 2950
(2010/06/21)
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- An efficient synthesis of substituted cytosines and purines under focused microwave irradiation
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A rapid nucleophilic displacement reaction of 6-chloropurine, 2-amino-6-chloropurine and 5-bromocytosine with various nucleophiles under focused microwave irradiation is described. Using this method, the desired products were obtained with the yields up to 99% in?a?short reaction time.
- Huang, Ling-Kuen,Cherng, Yen-Chih,Cheng, Yann-Ru,Jang, Jing-Pei,Chao, Yi-Ling,Cherng, Yie-Jia
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p. 5323 - 5327
(2008/02/01)
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- Synthesis of 6-alkyl- and arylamino-9-(tetrahydro-2-pyranyl)purines via 6-methylsulfonylpurine
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A series of six potential plant hormones, 6-alky- and arylamino-9- (tetrahydro-2-pyranyl)purines were prepared in three steps in 35 to 45% overall yield from 6-methylthiopurine via 6-methylsulfonylpurine.
- Villar, Jose Daniel Figueroa,Motta, Marita Almeida
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p. 1005 - 1015
(2007/10/03)
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- Synthesis of N6-substituted adenines from 3-methylxanthine
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A series of 6-arylalkyl(hetarylalkyl, cycloalkyl, carboxyalkyl)amino-7-benzyl-2-chloropurines have been synthesized from 3-methylxanthine via the reaction of the intermediate 7-benzyl-2,6-dichloropurine with amines and aminoacids. N6-benzyladenine, N6-(α-furfuryl)adenine (kinetin), and N-(purinyl)glycine have been obtained via the catalytic hydrogenation of 7-benzyl-6-benzyl(furfuryl, carboxymethyl)amino-2-chloropurines.
- Kochergin,Persanova,Aleksandrova
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p. 455 - 458
(2007/10/03)
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- Patch preparations for treating plants
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The following invention introduces a patch preparation for treating plants, whereas the patch preparations comprise a chemical layer composed of at least one agrochemically active compound, at least one adhesive and optionally, one or more additives. The components are dispersed in a matrix state on a substrate which are then introduced on the roots of the plant to be treated.
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- Purines. LXXIX. Synthesis and hydrolysis of 3-methoxyadenine and its N6-benzyl derivative leading to the corresponding 2-hydroxyadenines
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Methylation of adenine 3-oxide (8a) with MeI in AcNMe2 afforded 3- methoxyadenine (9a) in 44% yield. This compound (9a) underwent hydroxide-ion attack at the 2-position to give 2-hydroxyadenine (isoguanine) (10a) in 38% yield. A parallel reaction sequence starting from N6-benzyladenine 3-oxide (8c) and proceeding through N6-benzyl-3-methoxyadenine (9c) provided N6- benzyl-2-hydroxyadenine (10c) in 29% overall yield, together with a small amount of N6-benzyladenine (11c).
- Itaya, Taisuke,Kanai, Tae,Takada, Yasutaka,Kaneko, Miki,Yasuhara, Kensuke,Fujii, Tozo
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p. 554 - 556
(2007/10/03)
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- N-Nitrosobenzylmethylamine is activated to a DNA benzylating agent in rats
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The ability of rat tissues to activate the esophageal carcinogen, N- nitrosobenzylmethylamine (NBzMA), to a DNA benzylating intermediate was investigated. [3-3H]NBzMA was prepared and given to male F344 rats. Tissues were harvested 4 h after treatment, and DNA was isolated. HPLC analysis with radiochemical detection of chemical and enzymatic hydrolysates of DNA from liver and lung revealed the formation of benzyl adducts. Benzyl alcohol, N2- benzylguanine, 3-benzyladenine, N6-benzyladenine, and 7-benzylguanine were the major radioactive components in the hydrolysates. An unknown adduct was also observed. The adduct distribution was similar to that observed in [3- 3H]benzylnitroseurea ([3-3H]BzNU)treated calf thymus DNA. However, enzymatic hydrolysates of [3-3H]BzNU-treated DNA also contained significant levels of O6-benzyl-2'-deoxyguanosine (O6-BzdG). This radioactive adduct disappeared upon incubation of the DNA with a crude preparation of the repair protein, O6-alkylguanine-DNA alkyltransferase isolated from rat liver. These data provide evidence that O6-BzdG is probably rapidly repaired in vivo. No benzylation of esophageal mucosal DNA was detected. The level of DNA benzylation observed in tissues from [3-3H]NBzMA-treated rats was several orders of magnitude lower than the level of DNA methylation in these same tissues. Therefore, these data indicate that DNA benzylation plays a minor role, if any, in the carcinogenic activity of NBzMA.
- Peterson, Lisa A.
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- The Chemistry of N-Substituted Benzotriazoles. Part 4. A Novel and Versatile Method for the Mono-N-alkylation of Aromatic and Heteroaromatic Amines
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Mono-N-alkylation of aromatic and heteroaromatic amines is achieved in high yield by NaBH4 reduction of the adducts formed from benzotriazole, aliphatic aldehydes and the amines.Reaction of the same adducts with Grignard reagents gives N-(secondary alkyl)arylamines.Carboxy groups need no protection and nitro groups are unaffected.Adenine is mono-N-alkylated in high yield.
- Katritzky, Alan R.,Rachwal, Stanislaw,Rachwal, Bogumila
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p. 805 - 810
(2007/10/02)
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- INHIBITORS OF TWO ENZYMES WHICH METABOLIZE CYTOKININS
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Compounds which inhibit the natural metabolic inactivation of cytokinins are cosiderable physiological significance.In this study, inhibitors have been found for two enzymes which form glucose and alanine conjugates of cytokinin bases, namely, cytokinin 7-glucosyltransferase and β-(9-cytokinin)alanine synthase.The most effective inhibitors found for the former enzyme were the cytokinin analogues 3-methyl-7-n-pentylaminopyrazolopyrimidine, which acted competitively (Ki 22 μM), and the diaminopurine, 6-benzylamino-2-(2-hydroxyethylamino)-9-methylpurine (Ki 3.3 μM).However these compounds were ineffective as inhibitors of the cytokinin-alanine sythase which was inhibited competitively by IAA (Ki 70 μM) and related compounds, especially 5,7-dichloro-IAA (Ki 0.4 μM).Certain urea derivatives were moderately effective inhibitors of the enzymes (Ki ca 100 μM). Key Word Index - Cytokinins; metabolism; cytokinin 7-glucosyltransferase; β-(9-cytokinin)alanine synthase; N6-substituted adenines; auxins; indoleacetic acid.
- Parker, Charles W.,Entsch, Barrie,Letham, David S.
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p. 303 - 310
(2007/10/02)
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