- Genetic variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects identified by phenotyping for trimethylaminuria and found in a database of genome resources
-
The oxygenation of food-derived trimethylamine to its N-oxide is a representative reaction mediated by human flavin-containing monooxygenase 3 (FMO3). Impaired FMO3 enzymatic activity is associated with trimethylaminuria (accumulation of substrate), whereas trimethylamine N-oxide (metabolite) is associated with arteriosclerosis. We previously reported FMO3 single-nucleotide and/or haplotype variants with low FMO3 metabolic capacity using urinary phenotyping and the whole-genome sequencing of Japanese populations. Here, we further analyze Japanese volunteers with self-reported malodor and interrogate an updated Japanese database for novel FMO3 single-nucleotide and/or haplotype variants. After 3 years of follow up, seven probands were found to harbor the known impaired FMO3 variant p.(Gly191Cys) identified in the database or novel variants/haplotypes including p.(Met66Val), p.(Arg223Gln), p.(Glu158Lys;Glu308Gly;Arg492Trp), and p.(Glu158Lys;Glu308Gly;Pro496Ser). The known severe mutation p.(Cys197Ter) (a TG deletion) and four variants including p.(Tyr269His) and p.(Pro496Ser) were first detected in the updated genome panel. Among previously unanalyzed FMO3 variants, the trimethylamine/benzydamine N-oxygenation activities of recombinant p.(Met66Val), p.(Arg223Gln), p.(Tyr269His), p.(Glu158Lys;Glu308Gly;Arg492Trp), and p.(Glu158Lys;Glu308Gly;Pro496Ser) FMO3 variant proteins were severely decreased (Vmax/Km 10% of wild-type). Although the present novel mutations or alleles were relatively rare, both in self-reported Japanese trimethylaminuria sufferers and in the genomic database panel, three common FMO3 missense or deletion variants severely impaired FMO3-mediated N-oxygenation of trimethylamine.
- Shimizu, Makiko,Koibuchi, Natsumi,Mizugaki, Ami,Hishinuma, Eiji,Saito, Sakae,Hiratsuka, Masahiro,Yamazaki, Hiroshi
-
-
Read Online
- 13C GIAO DFT calculation as a tool for configuration prediction of N-O group in saturated heterocyclic N-oxides
-
Tropane, tropinone, pseudopelletierine and cocaine were oxidized in situ in a nuclear magnetic resonance (NMR) tube providing mixtures of exo/endo N-oxides. Observed 13C chemical shifts were correlated with values calculated by gauge-including atomic orbitals density functional theory (DFT) OPBE/6-31G* method using DFT B3LYP/6-31G* optimized geometries. The same method of 13C chemical shift calculation was applied on series of methyl-substituted 1-methylpiperidines and their epimeric N-oxides described in literature. The results show that using this undemanding calculation method enables assignment of configuration of N-O group in N-epimeric saturated heterocyclic N-oxides. The approach enables assigning of the configuration with high degree of certainty even if NMR data of only one isomer are available. An improved method of in situ oxidation of starting amines in an NMR tube is also described. Copyright
- Pohl, Radek,Potmischil, Francisc,Dracinsky, Martin,Vanek, Vaclav,Slavetinska, Lenka,Budesinsky, Milos
-
-
Read Online
- The observed and calculated 1H and 13C chemical shifts of tertiary amines and their N-oxides
-
A series of model tertiary amines were oxidized in situ in an NMR tube to amine N-oxides and their 1H and 13C NMR spectra were recorded. Next, the chemical shifts induced by oxidation (Δλ) were calculated using different GIAO methods investigating the influence of the method [Hartree-Fock (HF), Moeller-Plesset perturbation, density functional theory (DFT)], the functional applied in the DFT (B3LYP, BPW, OPBE, OPW91) and the basis set used [6-31G*, 6-311G**, 6-311 + + G** and 6-311 + + G(3df,3pd)]. The best results were obtained with the HF/6-311 + + G** and OPBE/6-311 + + G** methods. The computation/experiment comparison approach was used for the configuration prediction of chiral amine N-oxides-(R) and (S)-agroclavine-6-N-oxide.
- Pohl, Radek,Dracinsky, Martin,Slavetinska, Lenka,Budesinsky, Milos
-
-
Read Online
- CRYSTALLINE ANHYDROUS TRIMETHYLAMINE N-OXIDE
-
A rapid, efficient procedure for the preparation of pure, crystalline anhydrous trimethylamine N-oxide from the commercially available dihydrate form of the reagent is described.DMF serves to both allow the distillative removal of water as well as to provide an excellent medium for obtaining large crystals of the pure (mp 225-7oC (dec)), anhydrous material in excellent (94percent) yield.
- Soderquist, John A.,Anderson, Charles L.
-
-
Read Online
- Infrared matrix isolation studies of the trimethylamine oxide-hydrogen chloride complex
-
The reaction products of the codeposition of trimethylamine oxide and a HCl/Ar mixture are characterized by diffuse absorption in the region from 1850 to ca 3200 cm-1 and by a strong band at 1700 cm-1.These absorptions are assigned respectively to the O-H+ ...Cl- antisymmetric stretching and in-plane bending modes, which indicates that proton transfer to basic oxygen occurs.
- Mielke, Z.
-
-
Read Online
- Autoxidation of Trimethylamine in Aqueous Solutions
-
The autoxidation of trimethylamine in aqueous solutions has been studied at 100 deg C and at O2 pressures up to 153 atm.Trimethylamine N-Oxide is a major product.Its yield accounts for as much as, but never in excess of 50percent, the balance being Me2NH and HCONMe2.The reaction follows second-order kinetics, -d/dt= kPO2, where k= 8.7 x 10-7 atm-1 s-1.In solutions buffered with 0.1 N NaOH, the yield of Me3NO is reduced.These results are interpreted in terms of a rate-limiting electron-transfer reaction between Me3N and dioxygen, followed by reactions dictated by the radical ions, Me3N.+ and O2.- thus generated.It is noted that only one oxygen atom in the O2 molecule is incorporated into Me3NO, the other being used in the sacrificial oxidations to give other products.
- Chen, Michael J.,Linehan, John C.,Rathke, Jerome W.
-
-
Read Online
- SO2F2-mediated oxidation of primary and tertiary amines with 30% aqueous H2O2 solution
-
A highly efficient and selective oxidation of primary and tertiary amines employing SO2F2/H2O2/base system was described. Anilines were converted to the corresponding azoxybenzenes, while primary benzylamines were transformed into nitriles and secondary benzylamines were rearranged to amides. For tertiary amine substrates quinolines, isoquinolines and pyridines, their oxidation products were the corresponding N-oxides. The reaction conditions are very mild and just involve SO2F2, amines, 30% aqueous H2O2 solution, and inorganic base at room temperature. One unique advantage is that this oxidation system is just composed of inexpensive inorganic compounds without the use of any metal and organic compounds.
- Liao, Xudong,Zhou, Yi,Ai, Chengmei,Ye, Cuijiao,Chen, Guanghui,Yan, Zhaohua,Lin, Sen
-
supporting information
(2021/11/01)
-
- Tetrahydropyrrolization of Resveratrol and Other Stilbenes Improves Inhibitory Effects on DNA Oxidation
-
The inhibitory effect of resveratrol on DNA oxidation caused by 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH) was found to be enhanced if the C=C bond in resveratrol was converted into tetrahydropyrrole by reaction with azomethine ylide (CH2=N+(CH3)CH2?). This encouraged us to explore whether the inhibitory activities of other stilbenes could also be increased by the same method. We found that the inhibitory effects of the tetrahydropyrrole derivatives on AAPH-induced oxidation of DNA were higher than those of the corresponding stilbenes, because the tetrahydropyrrole motif can provide hydrogen atoms to be abstracted by radicals. Therefore, the tetrahydropyrrolization offered an advantage for enhancing the antioxidant effects of stilbenes. Notably, (CH3)3SiCH2N(CH3)CH2OCH3(in the presence of CF3COOH) and (CH3)3NO (in the presence of LiN(iPr)2) can be used to generate azomethine ylide for the tetrahydropyrrolization of stilbenes containing electron-withdrawing and -donating groups, respectively.
- Bao, Liang-Liang,Liu, Zai-Qun
-
p. 1617 - 1625
(2016/08/28)
-
- PYRAZOLE DERIVATIVES AND USES THEREOF AS INHIBITORS OF DLK
-
The present invention provides for compounds of formula 0 and various embodiments thereof, and compositions comprising compounds of formula 0 and various embodiments thereof. In compounds of formula 0, the groups R1A, R1B, R1C, R1D, R2, R3, R4, R5 and R6 have the meaning as described herein. The present invention also provides for methods of using compounds of formula 0 and compositions comprising compounds of formula 0 as DLK inhibitors and for treating neurodegeneration diseases and disorders.
- -
-
Page/Page column 115
(2015/07/07)
-
- SUBSTITUTED PYRAZOLES AND USES THEREOF
-
The present invention provides for compounds of formula 0 and various embodiments thereof, and compositions comprising compounds of formula 0 and various embodiments thereof. In compounds of formula 0, the groups R1A, R1B, R1C, R1D, R2, R3, R4, R5 and R6 have the meaning as described herein. The present invention also provides for methods of using compounds of formula 0 and compositions comprising compounds of formula 0 as DLK inhibitors and for treating neurodegeneration diseases and disorders.
- -
-
Paragraph 0378
(2015/07/02)
-
- Biomimetic oxidation reactions of a naked manganese(V)-Oxo porphyrin complex
-
The intrinsic reactivity of a manganese(V)-oxo porphyrin complex, a typically fleeting intermediate in catalytic oxidation reactions in solution, has been elucidated in a study focused on its gas-phase ion-chemistry. The naked high-valent MnV-oxo porphyrin intermediate 1 ([(tpfpp)Mn VO]+; tpfpp=meso-tetrakis(pentafluorophenyl)porphinato dianion), has been obtained by controlled treatment of [(tpfpp)Mn III]Cl (2-Cl) with iodosylbenzene in methanol, delivered in the gas phase by electrospray ionization and assayed by FT-ICR mass spectrometry. A direct kinetic study of the reaction with selected substrates, each containing a heteroatom X (X=S, N, P) including amines, sulfides, and phosphites, was thus performed. Ionic products arising from electron transfer (ET), hydride transfer (HT), oxygen-atom transfer (OAT), and formal addition (Add) may be observed, with a predominance of two-electron processes, whereas the product of hydrogen-atom transfer (HAT), [(tpfpp)MnIVOH]+, is never detected. A thermochemical threshold for the formation of the product radical cation allows an evaluation of the electron-transfer ability of a Mn V-oxo complex, yielding a lower limit of 7.85 eV for the ionization energy of gaseous [(tpfpp)MnIVO]. Linear free-energy analyses of the reactions of para-substituted N,N-dimethylanilines and thioanisoles indicate that a considerable amount of positive charge is developed on the heteroatom in the oxidation transition state. Substrates endowed with different heteroatoms, but similar ionization energy display a comparable reaction efficiency, consistent with a mechanism initiated by ET. For the first time, the kinetic acidity of putative hydroxo intermediates playing a role in catalytic oxidations, [(tpfpp)FeIVOH]+ and [(tpfpp)Mn IVOH]+, has been investigated with selected reference bases, revealing a comparatively higher basicity for the ferryl, [(tpfpp)Fe IVO], with respect to the manganyl, [(tpfpp)MnIVO], unit. Finally, the neat association reaction of 2 has been studied with various ligands showing that harder ligands are more strongly bound.
- Lanucara, Francesco,Crestoni, Maria Elisa
-
experimental part
p. 12092 - 12100
(2011/11/28)
-
- HYDROXYLAMMONIUM SALTS AS IONIC LIQUIDS
-
An ionic liquid containing cations of the formula: R1R2R3N+-OR4 wherein R1, R2, R3 and R4 are each independently selected from hydrogen and hydrocarbyl, the ionic liquid containing 1% or less of water by mass. Such ionic liquids may be used in particular as solvents for biocatalysis.
- -
-
Page/Page column 24
(2008/06/13)
-
- The reactions of ozone with tertiary amines including the complexing agents nitrilotriacetic acid (NTA) and ethylenediaminetetraacetic acid (EDTA) in aqueous solution
-
Using the stopped-flow technique, the rate constants of the reaction of ozone with a number of amines have been determined. While the protonated amines do not react with ozone, the free amines react with rate constants of around 106 dm3 mol-1 s-1 in the case of tertiary and secondary amines, while primary amines react more slowly. Mono-protonated EDTA reacts only with k = 1.6 × 105 and mono-protonated 1,4-diazabicyclo[2.2.2]octane (DABCO) with k = 3.5 × 103 dm3 mol-1 s-1. In aqueous solution, tertiary amines react with ozone mainly by forming the aminoxide and singlet dioxygen [O2(1Δg)] and to a lesser extent the secondary amine and the corresponding aldehyde, a reaction which can be partially suppressed by tert-butyl alcohol. These data suggest that O-transfer [aminoxide plus O2(1Δg)] is in competition with an electron transfer which leads to the amine radical cation and an ozonide radical. In water, the latter gives rise to ·OH which further reacts with the amine (and ozone). The amine radical cation deprotonates at a neighboring carbon. The resulting radical adds dioxygen. Subsequent elimination of O2·- and hydrolysis of the Schiff-base thus formed leads to the secondary amine and the corresponding aldehyde. In its reaction with ozone, O2·- yields further ·OH. Their reaction with the amines leads to the same intermediate as the free-radical pathway of ozone does, i.e. induces a chain reaction. This is interfered with by tert-butyl alcohol at the OH-radical stage. When complexed to Fe(III), EDTA reacts only very slowly with ozone (k = 330 dm3 mol-1 s-1). This explains why EDTA is not readily removed by ozonation in drinking-water processing.
- Munoz, Florinella,Von Sonntag, Clemens
-
p. 2029 - 2033
(2007/10/03)
-
- Selectivities in the oxidation of tertiary amines and pyridine derivatives by perfluoro cis-2,3-dialkyloxaziridines
-
When tertiary amines 1 are reacted with perfluoro cis-2,3- dialkyloxaziridines 2 at -60 °C corresponding N-oxides 3 are formed in high yields. The process is chemoselective and diastereoselective. The chemoselectivity in the reaction of alkenyl substituted pyridines is solvent dependent, attack occurring exclusively at the carbon-carbon double bond or at the nitrogen atom under protic and aprotic conditions, respectively. Lower selectivities were obtained when standard reagents were used.
- Arnone, Alberto,Metrangolo, Pierangelo,Novo, Barbara,Resnati, Giuseppe
-
p. 7831 - 7842
(2007/10/03)
-
- Selective Autoxidation of Electron-Rich Substrates under Elevated Oxygen Pressures
-
We report here the observation of a novel autoxidation pathway which occurs with electron-rich substrates.Tertiary amines, dialkyl thioethers, olefins, and alkynes under high oxygen pressures (>20 bars of O2), in polar solvents, and at elevated temperatures (>90 deg C) yield in good to excellent selectivity amine oxides, sulfoxides, and site-specific olefin and alkyne cleavage products, respectively.The results of mechanistic studies, including high oxygen pressure electrochemical studies, are discussed.A mechanism for this novel oxygenation reaction pathway that is consistent with the observed results is proposed.It involves an initial unfavorable electron transfer from the electron-rich substrate to oxygen to yield superoxide and the radical cation, which reacts with triplet oxygen to yield the oxygenated radical cation intermediate, a suspected potent oxidant.Electron transfer to the oxygenated radical cation from additional substrate (chain reaction) or superoxide yields a zwitterionic intermediate.This intermediate either reacts with additional substrate (O-atom transfer) to yield product (sulfoxide and N-oxide, in the case of thioethers and tertiary amines) or is converted with unimolecular reactivity to dioxetane-like (in the case of alkenes) or dioxetene-like (in the case alkynes) derived products.
- Correa, Paul E.,Hardy, Gordon,Riley, Dennis P.
-
p. 1695 - 1702
(2007/10/02)
-
- An Unprecedented Selective Autoxidation of Tertiary Amines to Amine Oxides
-
Tertiary amines have been found to react directly with molecular oxygen under high O2 pressures to give in an unexpected result the corresponding N-oxide in high yields.
- Riley, Dennis P.,Correa, Paul E.
-
p. 1563 - 1564
(2007/10/02)
-
- AMINE OXIDES-XIII IODINE COMPLEXES WITH NON-AROMATIC AMINE OXIDES
-
EDA-iodine complex with trialkylamine oxides in dichloromethane have been investigated spectrophotometrically.Thermodynamic (KADc,-ΔG0) and spectral (ΕADλ) characteristics of these complexes were determined.The absorption band of iodine in the visible region was blue-shifted with a variable maximum, depending on the structure of the amine oxide.The KADc and ΕADλ values were calculated using a modified method.A non-linear relationship KADc=(R), where R is the number of carbon atoms in the alkyl chain, was found.
- Devinsky, F.,Leitmanova, A.,Lacko, I.,Krasnec, L.
-
p. 5707 - 5710
(2007/10/02)
-
- Quantum Chemical Studies of Model Cytochrome P450 Oxidation of Amines. MNDO Pathways for Alkylamine Reactions with Singlet and Triplet Oxygen
-
Reaction pathways for oxidation of ammonia and mono-,di-,and trimethylamine by singlet and triplet oxygen atoms as models for cytochrome P450 enzymatic oxidation have been characterized by using the semiempirical molecular orbital method MNDO.Enthalpies of formation have been calculated for reactants, transition states, intermediates, and produts on closed shell and triplet pathways,and free energies of reaction and activation have been calculated from them.Energy minima and transition states have been verified by calculation of force constans.The results indicate a two-step,addition-rearrangement mechanism for nonradical oxidation leading to both N-hydroxy and N-methoxy products via N-oxide intermediates.While barriers to the rearrangement are higher than to N-oxide formation,the first step is determining the overall reaction in the gas phase.On a triplet surface, both α-C- and N-oxidation are competitive.N-Oxidation via an addition mechanism appears to be favored over on H-abstractionmechanism.However, in contrast to a closed-shell mechanism, no stable N-oxide radical intermediate is found, and the barrier to formation of N-hydroxy and N-methoxyl products on a triplet surface is grater.Additional gas phase, solution, and enzymatic studies, particulary focusing on identification of transient intermediates and products, are necessary to further distinguisch among these mechanisms.
- Goldblum, Amiram,Loew, Gilda H.
-
p. 4265 - 4272
(2007/10/02)
-
- Topical medicament preparations
-
Topical therapeutic compositions are disclosed which contain from about 0.1 to 70 percent by weight of a water-soluble tertiary amine oxide and a therapeutic agent selected from the group consisting of erythromycin, benzoyl peroxide, hydrocortisone, tetracycline, 5-fluorouracil, and propranolol. The amine oxide enhances penetration of the therapeutic agent into and through the skin.
- -
-
-
- Ruthenium Chloride Catalysed Oxidation of Tertiary Amines to Amine Oxides with Molecular Oxygen
-
Tertiary amines are catalytically oxidized with molecular oxygen in homogeneous solutions containing RuCl3*xH2O to afford as a major product the corresponding N-oxide, the first example of such an oxidation.
- Riley, Dennis P.
-
p. 1530 - 1532
(2007/10/02)
-
