Linked Life Data

11831907

Source:http://linkedlifedata.com/resource/pubmed/id/11831907

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-2-8
pubmed:abstractText
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, CH(3), OH, OCH(3), and NH(2), led to NO formation rates between 8 and 41% of that of NO formation from the natural NOS substrate, N(omega)-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 O(2) 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 N(omega)-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(triple bond)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 k(cat) value for NOS II-catalyzed oxidation of N-para-fluorophenyl N'-hydroxyguanidine was 80% of that found for NOHA, and its k(cat)/K(m) value was only 9-fold lower than that of NOHA. Interestingly, the K(m) value found for NOS II-catalyzed oxidation of N-(3-thienyl) N'-hydroxyguanidine was 25 microM, 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 para-methylphenyl 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
14
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
944-54
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
N-Aryl N'-hydroxyguanidines, a new class of NO-donors after selective oxidation by nitric oxide synthases: structure-activity relationship.
pubmed:affiliation
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris V, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't