- Preparation method of important intermediate (uracil-5-carboxylic acid) of medicine (avanafil)
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The invention discloses a preparation method of an important intermediate (uraciluracil-5-carboxylic acid) of a medicine (avanafil), and belongs to the technical field of drug synthesis. The preparation method is characterized in that the uraciluracil-5-carboxylic acid is prepared by adopting thymine as a starting material and using oxygen for further oxidation under the action of an active-carbon-loaded catalyst. The preparation method disclosed by the invention has the advantages of high yield, low cost, economic and environment-friendly effects and applicability to industrialization and thelike and is a synthesis method with industrial production value.
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Paragraph 0014-0020
(2018/09/08)
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- Molecular basis for the substrate specificity and catalytic mechanism of thymine-7-hydroxylase in fungi
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TET proteins play a vital role in active DNA demethylation in mammals and thus have important functions in many essential cellular processes. The chemistry for the conversion of 5mC to 5hmC, 5fC and 5caC catalysed by TET proteins is similar to that of T to 5hmU, 5fU and 5caU catalysed by thymine-7-hydroxylase (T7H) in the nucleotide anabolism in fungi. Here, we report the crystal structures and biochemical properties of Neurospora crassa T7H. T7H can bind the substrates only in the presence of cosubstrate, and binding of different substrates does not induce notable conformational changes. T7H exhibits comparable binding affinity for T and 5hmU, but 3-fold lower affinity for 5fU. Residues Phe292, Tyr217 and Arg190 play critical roles in substrate binding and catalysis, and the interactions of the C5 modification group of substrates with the cosubstrate and enzyme contribute to the slightly varied binding affinity and activity towards different substrates. After the catalysis, the products are released and new cosubstrate and substrate are reloaded to conduct the next oxidation reaction. Our data reveal the molecular basis for substrate specificity and catalytic mechanism of T7H and provide new insights into the molecular mechanism of substrate recognition and catalysis of TET proteins.
- Li, Wenjing,Zhang, Tianlong,Ding, Jianping
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p. 10026 - 10038
(2015/12/23)
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- The detrimental effect of orotic acid substitution in the peptide nucleic acid strand on the stability of PNA2:NA triple helices
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We have investigated the incorporation of C6 derivatives of uracil into polypyrimidine peptide nucleic acid oligomers. Starting with uracil-6-carboxylic acid (orotic acid), a peptide nucleic acid monomer compatible with Fmoc-based synthesis was prepared. This monomer then served as a convertible nucleobase whereupon treatment of the resin-bound methyl orotate containing hexamers with hydroxide or amines cleanly converted the ester to an orotic acid or orotamide-containing peptide nucleic acid. Peptide nucleic acid hexamers containing the C6-modified nucleobase hybridized to both poly(riboadenylic acid) and poly(deoxyriboadenylic acid) via triplex formation. Complexes formed with poly(riboadenylic acid) were more stable than those formed with poly(dexoyriboadenylic acid), as measured by temperature-dependent UV spectroscopy. However, both of these complexes were destabilized relative to the complexes formed by an unmodified peptide nucleic acid oligomers. Internal or doubly substituted hexamers are destabilized more strongly than a terminally substituted one, and the type of substitution (carboxamide, ester, carboxylic acid) affects the overall triplex stability. These results clearly show that incorporation of a C6-substituted uracil into polypyrimidine PNA is detrimental to triplex formation. We have also extended this chemistry to incorporate uracil-5-methylcarboxylate into a peptide nucleic acid hexamer. After on-resin conversion of the C5 ester to the 3-(N,N-dimethylamino)propylamide, significant stabilization of the triplex formed with poly(riboadenylic acid) was observed, which illustrates the compatibility of C5 substitution with peptide nucleic acid directed triple helix formation.
- Hudson, Robert H. E.,Wojciechowski, Filip
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p. 1731 - 1740
(2007/10/03)
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- Photochemical deamination and demethylation of 5-methylcytosine
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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.
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p. 745 - 750
(2007/10/03)
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- Stevioside analogs
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Analogs of the glycoside stevioside are disclosed. These materials have the formula STR1 wherein R is a simple physiologically acceptable noncarbohydrate polar organic group. The analogs are sweet and find use as sweeteners.
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- Intramolecular Influence of a Carboxylic Function on Platinium Blue Synthesis. A systematic Study of Complexes Originating from Acid Amides
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The use of acid amide as ligand for obtaining platinium blue has been investigated.While blue compounds are generally obtained by using the hydrolysis product of cis-dichlorodiammineplatinum(II) as platinum surce, with such ligands the reaction occurs very readily using potassium tetrachloroplatinate(II).The role of the carboxylic function which offers here a primary ligating site to platinum is evidenced.The compounds obtained have been characterized by UV-visible spectral measurments, Ce(IV) oxydative titration , ESR spectroscopy, and magnetic properties.Antitumoral activity toward leukemia L1210 and sarcoma 180 is reported for two of thesecompounds.As a first step for this antitumor study, these compounds have been found to be inactive toward Leukemia while they presnt intersting activity toward Sarcoma.
- Arrizabalaga, Philippe,Castan, Paule,Laurent, Jean-Pierre
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p. 4814 - 4818
(2007/10/02)
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- Glucosubstituented diterpenoid sweeteners
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Glucosubstituented diterpenoid compounds analogous to stevioside, rebaudosides C and A, steviolmonoside and steviolbioside but having their gluco units substituted with simple monoglycosidic polar groups and optionally having their C19 carboxyls as simple esters are disclosed. These materials are sweet and do not degrade under mammalian GI tract conditions.
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- Steviol compounds
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Analogs of the glycoside stevioside are disclosed. These materials have the formula STR1 wherein R1 and R2 are as follows: ______________________________________R1 R2______________________________________(CH2)3 SO3- M+ β-D-Sophorose(CH2)3 SO3- M+ (CH2)3 SO3- M+H (CH2)3 SO3- M+______________________________________ and M+ is a physiologically acceptable alkali metal cation.
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