130974-86-6Relevant articles and documents
Oxidations of Nω-hydroxyarginine analogues and various N-hydroxyguanidines by NO synthase II: Key role of tetrahydrobiopterin in the reaction mechanism and substrate selectivity
Moali,Boucher,Renodon-Corniere,Stuehr,Mansuy
, p. 202 - 210 (2001)
Oxidations of L-arginine 2, homo-L-arginine 1, their Nω-hydroxy derivatives 4 and 3 (NOHA and homo-NOHA, respectively), and four N-hydroxyguanidines, Nω-hydroxynor-L-arginine 5 (nor-NOHA), Nω-hydroxydinor-L-arginine 6 (dinor-NOHA), N-(4-chlorophenyl)-N'-hydroxyguanidine (8), and N-hydroxyguanidine (7) itself, by either NOS II or (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4)-free NOS II, have been studied in a comparative manner. Recombinant BH4-free NOS II catalyzes the oxidation of all N-hydroxyguanidines by NADPH and O2, with formation of NO2- and NO3- at rates between 20 and 80 nmol min-1 (mg of protein)-1. In the case of compound 8, formation of the corresponding urea and cyanamide was also detected besides that of NO2- and NO3-. These BH4-free NOS II-dependent reactions are inhibited by modulators of electron transfer in NOS such as thiocitrulline (TC) or imidazole (ImH), but not by Arg, and are completely suppressed by superoxide dismutase (SOD). They exhibit characteristics very similar to those previously reported for microsomal cytochrome P450-catalyzed oxidation of N-hydroxyguanidines. Both P450 and BH4-free NOS II reactions appear to be mainly performed by O2?- derived from the oxidase function of those heme proteins. In the presence of increasing concentrations of BH4, these nonselective oxidations progressively disappear while a much more selective monooxygenation takes place only with the N-hydroxyguanidines that are recognized well by NOS II, NOHA, homo-NOHA, and 8. These monooxygenations are much more chemoselective (8 being selectively transformed into the corresponding urea and NO) and are inhibited by Arg but not by SOD, as expected for reactions performed by the NOS FeII-O2 species. Altogether, these results provide a further clear illustration of the key role of BH4 in regulating the monooxygenase/oxidase ratio in NOS. They also suggest a possible implication of NOSs in the oxidative metabolism of certain classes of xenobiotics such as N-hydroxyguanidines, not only via their monooxygenase function but also via their oxidase function.
A NO donor type he Augmentin derivatives, preparation method and application (by machine translation)
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, (2017/08/31)
The invention provides a having the general formula (I) as shown in the structural formula of the compound, the compound has better NO release of the active, with better prospect of application, can be used for anti-inflammatory, anti-thrombotic, anti-platelet activity, reducing cholesterol and triglyceride levels and/or improve the high density lipoprotein levels, treatment of peripheral ischemia, diabetic vascular complications in or atherosclerosis. The invention also provides a method for preparing said compound. (by machine translation)
N-aryl N′-hydroxyguanidines, a new class of NO-donors after selective oxidation by nitric oxide synthases: Structure-activity relationship
Renodon-Cornière, Axelle,Dijols, Sylvie,Perollier, Céline,Lefevre-Groboillot, David,Boucher, Jean-Luc,Attias, Roger,Sari, Marie-Agnes,Stuehr, Dennis,Mansuy, Daniel
, p. 944 - 954 (2007/10/03)
The formation of nitric oxide (NO) was followed during the oxidation of 37 N-hydroxyguanidines or related derivatives, including 18 new N-aryl N′ -hydroxyguanidines, by recombinant inducible nitric oxide synthase (NOS II). Several N-aryl N′-hydroxyguanidines bearing a relatively small, electron-donating para subtituent, such as H, F, Cl, CH3, OH, OCH3, and NH2, led to NO formation rates between 8 and 41% of that of NO formation from the natural NOS substrate, Nω-hydroxy-L-arginine (NOHA). The characteristics of these reactions were very similar to those previously reported for the oxidation of NOHA by NOS: (i) the strict requirement of NOS containing (6R)-5,6,7,8-tetrahydro-L-biopterin, reduced nicotinamide adenine dinucleotide phosphate, and O2 for the oxidation to occur, (ii) the formation of NO and the corresponding urea in a 1:1 molar ratio, and (iii) a strong inhibitory effect of the classical NOS inhibitors such as Nω-nitro-L-arginine and S-ethyl-iso-thiourea. Structure-activity relationship studies showed that two structural factors are crucial for NO formation from compounds containing a C=NOH function. The first one is the presence of a monosubstituted N-hydroxyguanidine function, since disubstituted N-hydroxyguanidines, amidoximes, ketoximes, and aldoximes failed to produce NO. The second one is the presence of a N-phenyl ring bearing a relatively small, not electron-withdrawing para substituent that could favorably interact with a hydrophobic cavity close to the NOS catalytic site. The kcat value for NOS II-catalyzed oxidation of N-parafluorophenyl N′-hydroxyguanidine was 80% of that found for NOHA, and its kcat/Km value was only 9-fold lower than that of NOHA. Interestingly, the Km value found for NOS II-catalyzed oxidation of N-(3-thienyl) N′-hydroxyguanidine was 25 μM, almost identical to that of NOHA. Recombinant NOS I and NOS III also oxidize several N-aryl N′-hydroxyguanidines with the formation of NO, with a clearly different substrate specificity. The best substrates of the studied series for NOS I and NOS III were N-(para-hydroxyphenyl) and N-(meta-aminophenyl) N′-hydroxyguanidine, respectively. Among the studied compounds, the para-chlorophenyl and paramethylphenyl derivatives were selective substrates of NOS II. These results open the way toward a new class of selective NO donors after in situ oxidation by each NOS family.
