- Preparation method of vitamin B13
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The invention provides a preparation method of vitamin B13. The preparation method specifically comprises the following steps: step 1, carrying out ammonolysis reaction on maleic anhydride and urea toprepare an ammonolysis product; and step 2, oxidizing the ammonolysis product prepared in the step 1 under the catalysis of a catalyst to obtain vitamin B13. The method is a novel chemical reaction,and under the condition that liquid bromine is not used, the ammonolysis product of maleic anhydride and urea can be efficiently converted into vitamin B13. The method has the advantages of simple operation, cheap and easily available reagents, greenness, safety, high efficiency and environmental protection, and is suitable for industrial production.
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Paragraph 0018; 0022-0027
(2020/07/15)
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- Synthetic method of orotic acid
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The invention discloses a synthetic method of orotic acid, belonging to the technical field of chemical synthesis. The synthetic method of orotic acid comprises the following steps: reacting maleylurea with bromine, wherein the bromine is provided by a reaction of sodium bromide and hydrogen peroxide; and after a reaction of the hydrogen peroxide, the sodium bromide and the maleylurea is finished,adding strong alkali, and adding concentrated hydrochloric acid for acidification after the reaction is completed at 62-64 DEG C so as to obtain the orotic acid. According to the method, the hydrogenperoxide is used for oxidizing the sodium bromide, so elemental halogen used in an original process is replaced, and risks are greatly reduced; the method of applying intermediate bromine generated in situ to a reaction is adopted, so the reaction is uniform and mild, yield and product quality are improved, and the complexity of a production process is reduced; the sodium bromide can be recycled,so no hazardous waste is discharged; in the reaction of synthesizing the maleylurea, acetic acid can be distilled out through reduced-pressure distillation, so cyclic utilization of the acetic acid is achieved, and emission is reduced; and meanwhile, due to process improvement, the yield of the orotic acid is increased.
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Paragraph 0062-0071
(2020/08/22)
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- Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase
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Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 ? resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood–brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.
- Chen, Wuyan,He, Jiacheng,Hu, Qian,Huang, Jin,Huang, Ying,Liu, Zehui,Lu, Sisi,Lu, Weiqiang,Wang, Wanyan,Wu, Dang,Xu, Yechun,Ze, Shuyin
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- A orotic improved synthesis method
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The present invention discloses an improved synthesis of orotic method, which belongs to the field of organic chemical synthesis, Hein, chloroacetic acid and sodium hydroxide aqueous solution in particular in a microchannel reactor heating reaction to obtain a crude product of orotic, refining the crude product obtained after the pure orotic. The whole production process is carried out in a microchannel reactor, improves the reaction conversion and yield, the reaction yield of 90% or more.
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Paragraph 0032-0059
(2019/06/05)
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- Targeting of hematologic malignancies with PTC299, a novel potent inhibitor of dihydroorotate dehydrogenase with favorable pharmaceutical properties
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PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.
- Cao, Liangxian,Weetall, Marla,Trotta, Christopher,Cintron, Katherine,Ma, Jiyuan,Kim, Min Jung,Furia, Bansri,Romfo, Charles,Graci, Jason D.,Li, Wencheng,Du, Joshua,Sheedy, Josephine,Hedrick, Jean,Risher, Nicole,Yeh, Shirley,Qi, Hongyan,Arasu, Tamil,Hwang, Seongwoo,Lennox, William,Kong, Ronald,Petruska, Janet,Moon, Young-Choon,Babiak, John,Davis, Thomas W.,Jacobson, Allan,Almstead, Neil G.,Branstrom, Art,Colacino, Joseph M.,Peltz, Stuart W.
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- New synthesis method of orotic acid
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The invention belongs to the field of organic chemistry and discloses a new synthesis method of orotic acid, comprising the following steps: S1: enabling glycolonitrile and ammonia wate to react, thusobtaining a reaction system a in which a product is aminoacetonitrile A; S2: enabling aminoacetonitrile A and cyanate to react, thus obtaining a reaction system b in which a product is cyanomethylurea B; S3: performing condensation-rearrangement on cyanomethylurea B and glyoxylic acid in an alkaline solution to obtain orotic acid I. The method has the advantages of safe operation, low cost, lesspollution from three wastes, total reaction yield of 80% or above, and easy industrialization.
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Paragraph 0019; 0038; 0040; 0043; 0048
(2019/01/13)
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- Novel technology with introduced catalyst to optimize synthesis of dipyridamole
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The invention discloses a novel technology with an introduced catalyst to optimize the synthesis of dipyridamole, and belongs to the technical field of medical intermediates. According to the technology, in the step of oxidizing a methyl group of 6-methyl uracil into formic acid, a Co(OAc)2/HOAc/AIBN/O2 catalytic system is introduced, and the reaction yield is increased to 90 to 95%. In the step of reducing a nitro group of nitro-orotic acid into an amino group, activated copper powder is taken as the catalyst, the yield is more than 85%; and moreover, the environmental pollution and danger caused by sodium hydrosulfite are avoided. In the step of converting substituted hydroxyl group into substituted chlorine, SOCl12 and N,N-dimethyl formamide are introduced into the reaction system so as to reduce the environment pollution and the difficulty of post treatment. In the reactions of preparing 2,6-dichloro-4,8-bis(piperidine-1-yl)pyrimido[5,4-d]pyrimidine from perchloro pyrimido[5,4-d]pyrimidine, a CuI/PhNO2 catalytic system is introduced into the reaction system, the reaction yield reaches 95%, moreover, the operation is easy, and the treatment is simple. The provided technology increases the yield, reduces the cost, guarantees the safety, saves the energy, and meets the requirements of green reactions and modern chemical production.
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Paragraph 0023-0025
(2017/08/31)
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- Method for synthesizing orotic acid
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The invention discloses a method for synthesizing orotic acid, which comprises the following steps: firstly, condensing glycoluril and glyoxal as substrates in an alkaline solution and then oxidizing by introducing chlorine, obtaining an orotic acid crude product by a one-pot method, decolorizing and refining the crude product to obtain orotic acid. The method for synthesizing orotic acid provided by the invention takes glycoluril and glyoxal and chlorine as reaction raw materials, and has the advantages of simple reaction condition, low raw material cost, high yield, and high purity, and therefore is suitable for industrial mass production.
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Paragraph 0036; 0037
(2017/02/17)
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- Loop residues and catalysis in OMP synthase
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Residue-to-alanine mutations and a two-amino acid deletion have been made in the highly conserved catalytic loop (residues 100-109) of Salmonella typhimurium OMP synthase (orotate phosphoribosyltransferase, EC 2.4.2.10). As described previously, the K103A mutant enzyme exhibited a 104-fold decrease in kcat/KM for PRPP; the K100A enzyme suffered a 50-fold decrease. Alanine mutations at His105 and Glu107 produced 40- and 7-fold decreases in kcat/KM, respectively, and E101A, D104A, and G106A were slightly faster than the wild-type (WT) in terms of kcat, with minor effects on kcat/KM. Equilibrium binding of OMP or PRPP in binary complexes was affected little by loop mutation, suggesting that the energetics of ground-state binding have little contribution from the catalytic loop, or that a favorable binding energy is offset by costs of loop reorganization. Pre-steady-state kinetics for mutants showed that K103A and E107A had lost the burst of product formation in each direction that indicated rapid on-enzyme chemistry for WT, but that the burst was retained by H105A. Δ102Δ106, a loop-shortened enzyme with Ala102 and Gly106 deleted, showed a 104-fold reduction of kcat but almost unaltered KD values for all four substrate molecules. The 20% (i.e., 1.20) intrinsic [1′-3H]OMP kinetic isotope effect (KIE) for WT is masked because of high forward and reverse commitment factors. K103A failed to express intrinsic KIEs fully (1.095 ± 0.013). In contrast, H105A, which has a smaller catalytic lesion, gave a [1′-3H]OMP KIE of 1.21 ± 0.0005, and E107A (1.179 ± 0.0049) also gave high values. These results are interpreted in the context of the X-ray structure of the complete substrate complex for the enzyme [Grubmeyer, C., Hansen, M. R., Fedorov, A. A., and Almo, S. C. (2012) Biochemistry 51 (preceding paper in this issue, DOI 10.1021/bi300083p)]. The full expression of KIEs by H105A and E107A may result from a less secure closure of the catalytic loop. The lower level of expression of the KIE by K103A suggests that in these mutant proteins the major barrier to catalysis is successful closure of the catalytic loop, which when closed, produces rapid and reversible catalysis. (Graph Presented).
- Wang, Gary P.,Hansen, Michael Riis,Grubmeyer, Charles
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experimental part
p. 4406 - 4415
(2012/09/07)
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- CGRP ANTAGONISTS
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The present invention relates to new CGRP-antagonists of general formula I wherein U, V, X, Y, R1, R2 and R3 are defined as stated hereinafter, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
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Page/Page column 95-96
(2011/04/18)
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors
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Plasmodium falciparum NDH2 (pfNDH2) is a non-proton pumping, rotenone-insensitive alternative enzyme to the multi-subunit NADH:ubiquinone oxidoreductases (Complex I) of many other eukaryotes. Recombinantly expressed pfNDH2 prefers coenzyme CoQ0 as an acceptor substrate, and can also use the artificial electron acceptors, menadione and dichlorophenol-indophenol (DCIP). Previously characterized NDH2 inhibitors, dibenziodolium chloride (DPI), diphenyliodonium chloride (IDP), and 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ) do not inhibit pfNDH2 activity. Here, we provide evidence that HDQ likely targets another P. falciparum mitochondrial enzyme, dihydroorotate dehydrogenase (pfDHOD), which is essential for de novo pyrimidine biosynthesis.
- Dong, Carolyn K.,Patel, Vishal,Yang, Jimmy C.,Dvorin, Jeffrey D.,Duraisingh, Manoj T.,Clardy, Jon,Wirth, Dyann F.
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supporting information; scheme or table
p. 972 - 975
(2009/08/15)
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- SMALL MOLECULE INHIBITORS OF PLASMODIUM FALCIPARUM DIHYDROOROTATE DEHYDROGENASE
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Inhibitors of dihydroorotate dehydrogenase (DHODH) for the Plasmodium enzyme have been identified and characterized. The inhibitors have high specificity, submicromolar efficacy against cultured parasite strains, exhibit drug-like properties, and are not overtly cytotoxic.
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Page/Page column 3-4; 23-24; 52-53; 1/6; 2/6
(2010/01/29)
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- Brequinar derivatives and species-specific drug design for dihydroorotate dehydrogenase
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Therapeutic agents brequinar sodium and leflunomide (Arava) work by binding in a hydrophobic tunnel formed by a highly variable N-terminus of family 2 dihydroorotate dehydrogenase (DHODH). The X-ray crystallographic structure of an analog of brequinar bound to human DHODH was determined. In silico screening of a library of compounds suggested another subset of brequinar analogs that do not inhibit human DHODH as potentially effective inhibitors of Plasmodium falciparum DHODH.
- Hurt, Darrell E.,Sutton, Amanda E.,Clardy, Jon
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p. 1610 - 1615
(2007/10/03)
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- Multiple states of the Tyr318Leu mutant of dihydroorotate dehydrogenase revealed by single-molecule kinetics
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Dihydroorotate dehydrogenase (DHOD) from Escherichia coli is a monomeric membrane-associated flavoprotein that catalyzes the oxidation of dihydroorotate to orotate. By using confocal fluorescence spectroscopy on the highly fluorescent Tyr318Leu DHOD mutant, we studied the catalytic turnover of single enzyme molecules through the characteristic on-off fluorescence signal, which corresponds to flavin mononucleotide (FMN) interconverting between the oxidized and reduced states during turnover. Our single-molecule data provide evidence of a distinct static heterogeneity in the enzymatic activity, with some molecules going through the on-off cycles 5-fold faster than others, however, there is no detectable dynamic disorder in DHOD turnover. When 0.1% reduced Triton X-100, a detergent that more closely simulates the natural membrane environment, is added, our data suggest the degree of static molecular heterogeneity is reduced. The observation of static heterogeneity suggests that the enzyme, which associates with the membrane in vivo, is present in distinct conformations that result in different catalytic efficiencies. The alternate conformations are most likely the result of the loss of van der Waals or other interactions between tyrosine 318 and FMN in the catalytic site with the mutation of Tyr318Leu, which disrupts the native structure of wild-type DHOD.
- Shi, Jue,Palfey, Bruce A.,Dertouzos, Joe,Jensen, Kaj Frank,Gafni, Ari,Steel, Duncan
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p. 6914 - 6922
(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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- Indolo[2,1-biquinazoline-6,12-dione antibacterial compounds and methods of use thereof
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Methods, compounds and compositions are provided form inhibiting the growth of pathogenic mycobacteria in vitro and of treatment of pathogenic mycobacterial infections in vivo using indolo[2,1-b]quinazoline-6,12-dione compounds of the formula (I): STR1 wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, and the pharmaceutically acceptable salts thereof. The methods, compounds and compositons are particularly useful for inhibiting the growth of Mycobacterium tuberculosis, and may be used alone, or in combination with other anti-Mycobacterium tuberculosis agents, such as isoniazid, rifampin, pyrazinamide, rifabutin, streptomycin and ciprofloxacin, to provide new agents for the treatment of tuberculosis, including multidrug-resistant tuberculosis (MDRTB).
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- Formation of N-Carbamoylaspartic Acid and Its Cyclisation to Orotic Acid
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The stereochemistries of the reactions between cyanate and aspartic acid and 3-methylaspartic acid have been examined.The product of the first reaction, N-carbamoylaspartic acid 3, can cyclise to give either dihydroorotic acid 5 or 5-carboxymethylmydantoin 4.Acid catalysed cyclisation gives the latter while catalysis by the enzyme dihydroorotase gives the former.Introduction of a double bond into 3 changes the course of non-enzymatic cyclisation and a six-membered ring compound orotic acid 1 is the product.It is proposed that the double bond prevents intramolecular hydrogen bonding.
- Bruce, Michael J.,Butler, Anthony R.,Russell, Kate V.
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p. 319 - 322
(2007/10/02)
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- Water dispersion containing ultrafine particles of organic compounds
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A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
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- Mitomycin derivatives
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Mitomycin derivatives containing substituted dithioethylamino groups at the 7th position are provided. The mitomycin derivatives according to the present invention are superior to mitomycin C with respect to their improved anti-tumour activity and toxicity. More particularly, they exhibit a wider tolerance of dosage against Sarcoma 180A solid tumour as well as a better survival time and weaker bone marrow supression against P388.Furthermore, certain compounds exhibit a high water-solubility which is advantageous for pharmaceutical purposes. Excellent anti-tumour agents may readily be prepared by using the derivatives of the present invention.
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- Processes for preparing 4-amino-3-imidazolin-2-one and (2-methoxy-2-iminoethyl)urea
-
4-Amino-3-imidazolin-2-one and (2-methoxy-2-iminoethyl)urea are valuable intermediates for the production of pharmacologically active compounds.
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- Stereoselectivity in the Enzymatic Oxidation and Nonenzymatic Hydrogen-Exchange Reactions of Dihydroorotate
-
(S)-5,6-Dihydroorotate (1) undergoes a stereoselective hydrogen-exchange reaction with solvent deuterons in deuterium oxide buffer (100 mM NaPi pD 7.8, 37 deg C).High-field (1)H NMR analysis of the exchange reveals the formation of (5R,6S)-dihydroorotate (3) in an apparent first-order process (kobsd=5.4E-3 h-1, 37 deg C).Deuterium incorporation into the 5-pro-S position of 1 is also observed; pro-S exchange, however, occurs considerably more slowly (kobsd=4.8E-4 h-1, 37 deg C) than does pro-R exchange.Stereoselective exchange was also seen for methyl (S)-dihydroorotate (6) and for 6-methyl-(R,S)-dihydrouracil (7), athough these reactions are only modestly stereopreferential.We have capitalized on this stereochemical preference for 5-pro-R hydrogen exchange by preparing two diastereomers of deuterium-enriched dihydroorotates, 3 (from 1 in D2O buffer) and 5 (from (S)-dihydroorotate 4 in H2O buffer).These chirally deuterated dihydroorotates were used to elucidate the stereochemical course of the reaction (1->2) catalyzed by the beef liver mitochondrial dihydroorotate dehydrogenase (EC 1.3.3.1).Enzymatic oxidation was readily followed by high-field (1)H NMR spectrometry; the data show that the enzyme is absolutely stereoselective with reference to the diastereotopic C5 center.Only the pro-S hydrogen (or deuteron) is lost from C5 during conversion of dihydroorotate to orotate, thereby describing a trans oxidation of substrate.Thus, we report the interesting observation that enzymatic processing of dihydroorotate (1->2) shows stereoselectivity at C5 opposite to that of the nonenzymatic C5-hydrogen exchange (1->3).These results are examined with reference to the conformational, stereoelectronic, and electrostatic factors that may influence the stereochemical course of both the enzyme-catalyzed and nonenzymatic reactions.
- Keys, Loren D. III,Johnston, Michael
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p. 486 - 492
(2007/10/02)
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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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