- Substrate specificity of E. coli uridine phosphorylase. Further evidences of high-syn conformation of the substrate in uridine phosphorolysis
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Twenty five uridine analogues have been tested and compared with uridine with respect to their potency to bind to E. coli uridine phosphorylase. The kinetic constants of the phosphorolysis reaction of uridine derivatives modified at 2′-, 3′- and 5′-positions of the sugar moiety and 2-, 4-, 5- and 6-positions of the heterocyclic base were determined. The absence of the 2′- or 5′-hydroxyl group is not crucial for the successful binding and phosphorolysis. On the other hand, the absence of both the 2′- and 5′-hydroxyl groups leads to the loss of substrate binding to the enzyme. The same effect was observed when the 3′-hydroxyl group is absent, thus underlining the key role of this group. Our data shed some light on the mechanism of ribo- and 2′-deoxyribonucleoside discrimination by E. coli uridine phosphorylase and E. coli thymidine phosphorylase. A comparison of the kinetic results obtained in the present study with the available X-ray structures and analysis of hydrogen bonding in the enzyme-substrate complex demonstrates that uridine adopts an unusual high-syn conformation in the active site of uridine phosphorylase.
- Alexeev,Sivets,Safonova,Mikhailov
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- Prebiotic phosphorylation of 2-thiouridine provides either nucleotides or DNA building blocks via photoreduction
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Breakthroughs in the study of the origin of life have demonstrated how some of the building blocks essential to biology could have been formed under various primordial scenarios, and could therefore have contributed to the chemical evolution of life. Missing building blocks are then sometimes inferred to be products of primitive biosynthesis, which can stretch the limits of plausibility. Here, we demonstrate the synthesis of 2′-deoxy-2-thiouridine, and subsequently 2′-deoxyadenosine and 2-deoxyribose, under prebiotic conditions. 2′-Deoxy-2-thiouridine is produced by photoreduction of 2,2′-anhydro-2-thiouridine, which is in turn formed by phosphorylation of 2-thiouridine—an intermediate of prebiotic RNA synthesis. 2′-Deoxy-2-thiouridine is an effective deoxyribosylating agent and may have functioned as such in either abiotic or proto-enzyme-catalysed pathways to DNA, as demonstrated by its conversion to 2′-deoxyadenosine by reaction with adenine, and 2-deoxyribose by hydrolysis. An alternative prebiotic phosphorylation of 2-thiouridine leads to the formation of its 5′-phosphate, showing that hypotheses in which 2-thiouridine was a key component of early RNA sequences are within the bounds of synthetic credibility.
- Xu, Jianfeng,Green, Nicholas J.,Gibard, Clémentine,Krishnamurthy, Ramanarayanan,Sutherland, John D.
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p. 457 - 462
(2019/04/08)
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- Preparation method of uracil
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The invention discloses a preparation method of uracil. The method comprises the following steps: (a) enabling ethyl formate, ethyl acetate and sodium methylate to react so as to prepare sodium (E)-3-ethoxy-3-oxoprop-1-en-1-olate; (b) adding thiourea and ethyl acetate into the sodium (E)-3-ethoxy-3-oxoprop-1-en-1-olate, heating for carrying out a reaction, and acidizing by using hydrochloric acid to obtain thiouracil; (c) adding alkali and ethanol into the thiouracil, cooling and then dropwise adding a hydrogen peroxide water solution into the cooled mixture; after that, heating for carrying out a reaction to obtain the uracil. According to the technology for preparing the uracil by using the thiourea as a raw material, the used raw materials such as ethyl formate, the ethyl acetate, the thiourea and hydrogen peroxide are chemical products which are common, easy to obtain and low in price, so that the production cost is lower. The preparation method of the uracil is simple, convenient and fast to operate and high in yield, thus being suitable for large-scale industrial production.
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Paragraph 0010; 0022; 0023; 0024
(2017/08/30)
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- A prebiotically plausible synthesis of pyrimidine β-ribonucleosides and their phosphate derivatives involving photoanomerization
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Previous research has identified ribose aminooxazoline as a potential intermediate in the prebiotic synthesis of the pyrimidine nucleotides with remarkable properties. It crystallizes spontaneously from reaction mixtures, with an enhanced enantiomeric excess if initially enantioenriched, which suggests that reservoirs of this compound might have accumulated on the early Earth in an optically pure form. Ribose aminooxazoline can be converted efficiently into α-ribocytidine by way of 2,2'-anhydroribocytidine, although anomerization to β-ribocytidine by ultraviolet irradiation is extremely inefficient. Our previous work demonstrated the synthesis of pyrimidine β-ribonucleotides, but at the cost of ignoring ribose aminooxazoline, using arabinose aminooxazoline instead. Here we describe a long-sought route through ribose aminooxazoline to the pyrimidine β-ribonucleosides and their phosphate derivatives that involves an extraordinarily efficient photoanomerization of α-2-thioribocytidine. In addition to the canonical nucleosides, our synthesis accesses β-2-thioribouridine, a modified nucleoside found in transfer RNA that enables both faster and more-accurate nucleic acid template-copying chemistry.
- Xu, Jianfeng,Tsanakopoulou, Maria,Magnani, Christopher J.,Szabla, Rafa?,?poner, Judit E.,?poner, Ji?í,Góra, Robert W.,Sutherland, John D.
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p. 303 - 309
(2017/04/03)
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- Studies on the synthesis of N′-acetyl AZA-analogues of Ganciclovir - Unexpected liability of N′-(2-hydroxyethyl)-azanucleosides under basic conditions
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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
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experimental part
p. 768 - 785
(2011/05/04)
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- Comparative studies for selective deprotection of the N-arylideneamino moiety from heterocyclic amides: Kinetic and theoretical studies
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The kinetics, product analysis and theoretical studies for selective deprotection of N-arylideneamino pyridone, pyrimidinone and triazinone systems were carried out. Their reactivities were compared with each other and with related compounds previously studied. This reaction represents an efficient, clean and general synthetic procedure for the protection and selective synthesis of potential biologically active pyridines, pyrimidines and triazines and their derivatives.
- George, Bobby J.,Dib, Hicham H.,Abdallah, Mariam R.,Ibrahim, Maher R.,Khalil, Nasser S.,Ibrahim, Yehia A.,Al-Awadi, Nouria A.
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p. 1182 - 1192
(2007/10/03)
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- Solid-phase synthesis of 4(1H)-quinolone and pyrimidine derivatives based on a new scaffold - Polymer-bound cyclic malonic acid ester
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An efficient method for the preparation of polymer-bound cyclic malonic acid ester starting from Merrifield resin has been developed. Reaction of the resin-bound cyclic malonic acid ester with triethyl orthoformate and subsequent double substitution with
- Huang, Xian,Liu, Zhanxiang
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p. 6731 - 6737
(2007/10/03)
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- Composition of matter having bioactive properties
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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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- New 1,3-diazadienes used in heterocyclic synthesis
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The synthesis of dihydropyrimidines, dihydropyrimidinones and thiadiazine-1,1-dioxides starting from neutral or cationic 2-methylthio-1,3- diazadienes is described. Addition of H2S followed by loss of methanethiol led to the corresponding thiocarbonyl compounds.
- Friot, Celine,Reliquet, Alain,Reliquet, Francoise,Meslin, Jean Claude
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p. 695 - 702
(2007/10/03)
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- Synthesis and structure of norbornane/ene-fused thiouracils and thiazino[3,2-a]pyrimidinones
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Ethyl diexo- 3-aminobicyclo[ 2.2.1]heptane- and -hept-5-ene-2- carboxylares (1a,b) and the diendo derivatives were transformed with thiophosgene to the isothiocyanates (2a,b and 3a, b) and then cyclized to the norbornane/enecondensed 2-thioxopyrimidin-4-ones (4a, b and 5a, b). On heating, the norbornene compounds (4b and 5b) furnished thiouracil (6) via cyelopentadiene elimination. With dimethyl acetylenedicarboxylate, the thioxopyrimidinones (4a,b) and (5a,b) form angularly-fused [1,3]thiazino[3,2- a]pyrimidinones (7a,b and 8a,b). On heating, 7b decomposes to give 3-methyl- 2,3-dihydro-2-thioxo-4(1H)-pyrimidinone (9) in a retro Diels-Alder process by methyl migration and splitting-off of cyclopentadiene. The structures were elucidated by IR and NMR spectroscopies, with DNOE, DEPT and 2D-HSC techniques.
- Stajer, Geza,Szabo, Angela E.,Sohar, Pal
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p. 1849 - 1854
(2007/10/03)
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- FUSED-SKELETON SATURATED SIX-MEMBERED 1,3-N,O, N,N AND N,S HETEROCYCLES, FUSED-SKELETON ARYL-SUBSTITUTED SATURATED ISOINDOLONES
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In the introduction, a brief survey is given of the main types of fused-skeleton saturated six-membered 1,3-heterocycles serving as model compounds in our earlier investigations and as starting compounds in the present studies.The synthesis and conformational analysis of aryl-substituted fused-skeleton saturated 1,3-oxazines and of aryl-substituted hetero-condensed saturated isoindolones are treated. cis-trans isomerization in the saturated isoindolone moiety of the resulting tricyclic, tetracyclic and pentacyclic systems is discussed in connection with the ring-closure reactions of cis- and trans-1,2-disubstituted 1,2- and 1,3-difunctional alicyclic compounds to give alicycle-fused six-membered 1,3-heterocycles.The cycloaddition reactions of dihydro-1,3 and 3,1-oxazines and the conformations of the alicycle-fused tetrahydrooxazine-azetidinone derivatives obtained are presented.Methods are given for the preparation of saturated thiazolo- and thiazinoquinazolinones.Unambiguous, mainly one-pot syntheses for the preparation of 1,3-heterocycles by a retro Diels-Alder method are discussed.
- Bernath, G.
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p. 509 - 530
(2007/10/02)
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- 2-Thio derivatives of dUrd and 5-fluoro-dUrd and their 5'-monophosphates: Synthesis, interaction with tumor thymidylate synthase, and in vitro antitumor activity
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A convenient synthesis of 5-fluoro-2-thiouracil (11) is based on hydrolytic deamination of 5-fluoro-2-thiocytosine (9). Lewis acid-catalyzed condensation of di-TMS-5-fluoro-2-thiouracil (13) or di-TMS-2-thiouracil (14) with 2-deoxy-3,5-di-O-p-toluyl-D-ribofuranosyl chloride (15) led to mixtures of the β- and α-anomers of 3',5'-toluylated 2'-deoxy-5-fluoro-2-thiouridine (16 and 18) or 2'-deoxy-2-thiouridine (17 and 19), each of which was deblocked with MeOH-NH3 to give the desired free anomeric nucleoside pairs 1, 5 and 3, 7, respectively. These were selectively converted to the corresponding 5'-monophosphates 2, 6 and 4, 8, with the aid of the wheat shoot phosphotransferase system. Conformations of the nucleosides 1, 3, 5, 7 are deduced from 1H NMR spectra, and circular dichroism spectra for nucleotide anomeric pairs 2, 6 and 4, 8 are reported. Whereas β-2-thio-dUMP (4) was a good substrate (K(m) ? 10-5 M), β-5-fluoro-2-thio-dUMP (2) proved to be a potent competitive, slow-binding inhibitor (K(i) ? 10-8 M) of the purified enzymes from Ehrlich ascites carcinoma and L1210 cells. The α-anomer 6 was a weak inhibitor, with K(i) in the mM range, and its congener 8 hardly interacted with the enzyme. The β-anomer 1 exhibited antitumor activity in a mouse leukemic cell line L5178Y (IC50 ? 10-6 M), hence 40- 100-fold weaker than 5-fluoro-dUrd. Its α-anomer 5 was 10-fold less active, but exhibited at least 10-fold higher selectivity with respect to the tumor cells than the β-anomer 1.
- Bretner,Kulikowski,Dzik,Balinska,Rode,Shugar
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p. 3611 - 3617
(2007/10/02)
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- QUINAZOLINONE, TRIAZOLINONE AND PYRIMIDINONE ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED BENZYL ELEMENT
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Substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives of the Formula I are useful as angiotensin II antagonists. STR1
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- Boron-Containing Thiouracil Derivatives for Neutron-Capture Therapy of Melanoma
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Boron-containing derivatives of 2-thiouracil and 2,4-dithiouracil and the corresponding 6-propyl compounds, containing a dihydroxyboryl group in the 5-position, have been prepared.These compounds accumulate in B16 melanoma in mice in concentrations up to 30 μg of boron per gram tissue.The uptake persists.The toxicity of both 2-thiouracil derivatives is low.These compounds are therefore good candidates for boron neutron-capture therapy of malignant melanoma.
- Tjarks, Werner,Gabel, Detlef
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p. 315 - 319
(2007/10/02)
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- SYNTHESIS OF 1,3-DIOXIN-4-ONES AND THEIR USE IN SYNTHESIS. XI. 2,2-DIMETHYL-1,3-DIOXIN-4-ONE AS A SYNTHETIC EQUIVALENT OF FORMYLKETENE: SYNTHESIS OF HETEROCYCLIC COMPOUNS
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Cycloaddition of formylketene generated in situ by thermolysis of 2,2-dimethyl-1,3-dioxin-4-one with N-benzhydrylidenebenzylamine yields 3-benzyl-2,2-diphenyl-1,3-oxazin-4-one.Analogous reactions with a carbodiimide, cyanamide, and keteneacetal afford the corresponding 4 + 2 cycloadducts.Reaction of formylketene with 3-amino-2-butenamides affords 4-hydroxy-2-pyridones having a C-2 unit at the 3-position.Keywords: 1,3-dioxin-4-one;formylketene; cycloaddition;1,3-oxazin-4-one; 4-pyrone; 3-acetyl-4-hydroxy-2-pyridone; thermolysis; uracil derivative.
- Sato, Masayuki,Yoneda, Naoki,Kaneko, Chikara
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p. 621 - 627
(2007/10/02)
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- Improved One-Step Procedure for the Preparation of 1-Substituted and 1,3-Disubstituted Uracils and 2-Thiouracils
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A convenient one-pot procedure for the synthesis of 1-substituted and 1,3-disubstituted uracils and 2-thiouracils consists of acylation of ureas or thioureas with methyl 3,3-dimethoxypropanoate in the presence of a strong base, and acidic work-up.The yields range from 36 to 99percent.In all cases, only one regioisomer is isolated.
- Winckelmann, Ib,Larsen, Erik H.
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p. 1041 - 1044
(2007/10/02)
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- NEW SYNTHESIS OF URACIL AND 2-THIOURACIL
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Uracil (4) and 2-thiouracil (5) were easily obtained from Meldrum's acid and urea or thiourea in two steps.
- Cassis, R.,Tapia, R.,Valderrama, J. A.
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p. 961 - 966
(2007/10/02)
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- Synthetic Routes to Thiazolopyrimidin-7-ones via 1-Allyl-2-thiouracil
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The reaction of 1-allyl-2-thiouracil (4) with I2-AgOAc in refluxing AcOH proceeds to 2-methyl-7H-thiazolopyrimidin-7-one (5) via a series of intramolecular transformations.The intermediates, 2-iodomethyl-2,3-dihydro-7H-thiazolopyrimidin-7-one hydroiodide (6) and 2,3-dihydro-2-methylene-7H-thiazolopyrimidin-7-one (10), were investigated.The syntheses are also described of 1-allyl-5-bromo-2-thiouracil (9), 2-acetoxymethyl- (11) and the hydrobromide of 2-bromomethyl- (14)7H-thiazolopyrimidin-7-ones.
- Skaric, Vinko,Skaric, Djurdja,Cizmek, Ankica
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p. 2221 - 2226
(2007/10/02)
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- NOVEL RING TRANSFORMATION REACTIONS AND THEIR APPLICATIONS TO THE SYNTHESES OF POTENTIAL ANTICANCER HETEROCYCLIC COMPOUNDS
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Novel heterocyclic ring trasformation reactions developed recently in our laboratory are described.They include pyrimidine to pyrimidine, pyrimidine to pyridine transformations.Also discussed are novel one-step procedures for conversion of 1,3-dimethyluracil derivatives into the pyridopyrimidine system.Some applications of these novel reactions to the syntheses of compounds of biological interest are also described.
- Watanabe, K. A.,Su, T.-L.,Pankiewicz, K. W.,Harada, K.
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p. 289 - 307
(2007/10/02)
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- REACTIONS OF ETHYL 2-ALKYL-3-OXOBUTANOATE WITH THIOUREA AND METHYLTHIOUREA
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The reaction of ethyl-3-oxobutanoate with N-methylthiourea in alkoxide medium gives a mixture (1:20) of 1,6-dimethyl-2-thiouracil and 3,6-dimethyl-2-thiouracil: the latter isomer has been isolated from the mixture and the former isomer has been prepared by independent synthesis.Dissociation constants of ethyl 2-alkyl-3-oxobutanoates (alkyl = methyl, butyl or isopropyl) have been measured in methanol.Reaction of these esters with thiourea and N-methylthiourea gives the corresponding alkyl derivatives of 6-methyl-2-thiouracil.Kinetics of these reactions have been measured in methoxide medium.Effects of the alkyl groups on the reaction rates have been investigated, and a reaction mechanism is suggested.
- Kavalek, Jaromir,Machacek, Vladimir,Sterba, Vojeslav
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p. 1872 - 1877
(2007/10/02)
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- Pyrimidine to pyrimidine transformation process
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There is provided a novel process for pyrimidine to pyrimidine transformations by the displacement of the 1,2,3-portion of a pyrimidine by a 1,3-ambident nucleophile. The novel process requires that the 1 and 3 nitrogens of the pyrimidine moiety be substituted. The novel process makes available, inter alia, novel uracils, simple methods of radioisotopically labeling pyrimidine nuclei, a simple and inexpensive method of preparing the important antiviral and antileukemic material pseudoisocytidine and its new active analog 2'-deoxypseudoisocytidine.
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