Document Detail

A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.
MedLine Citation:
PMID:  18247523     Owner:  NLM     Status:  MEDLINE    
Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-( N-nitroso-2-imidazolinyl)benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37 degrees C ( kobs = 6.25 x 10 (-5) s (-1) in 0.5 M acetate buffer with a 10 * [NO2(-)] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations <3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.
Richard N Loeppky; Jianzheng Shi; Charles L Barnes; Sailaja Geddam
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-02-02
Journal Detail:
Title:  Chemical research in toxicology     Volume:  21     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-19     Completed Date:  2008-04-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  295-307     Citation Subset:  IM    
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
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MeSH Terms
Antihypertensive Agents / chemistry*
Diazonium Compounds / chemistry*
Nitrites / chemistry*
Nitroso Compounds / chemical synthesis
Tolazoline / chemistry*
Grant Support
Reg. No./Substance:
0/Antihypertensive Agents; 0/Diazonium Compounds; 0/Ions; 0/Nitrites; 0/Nitroso Compounds; 59-98-3/Tolazoline

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