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Absolute Configuration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol Formed Metabolically From 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

Absolute Configuration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol Formed Metabolically From 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

S S Hecht, T E Spratt, N Trushin

Carcinogenesis. 1997 Sep;18(9):1851-4.

PMID: 9328186

Abstract:

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is an important metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Using the chiral derivatizing agent, (R)-(+)-alpha-methylbenzyl isocyanate [(R)-(+)-MBIC], previous work has shown that the enantiomeric ratio of metabolically formed NNAL and its glucuronide derivative may be species dependent. However, the absolute configuration of such NNAL has not been previously reported. Synthetically prepared racemic NNAL was converted to diastereomeric esters by reaction with (R)-(+)- and (S)-(-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) chloride (Mosher's reagent) and the products were characterized by 1H-NMR. Based on chemical shift data, the absolute configuration of NNAL in each diastereomeric ester was assigned. Hydrolysis of (R)-NNAL-(R)-MTPA gave (R)-NNAL. This was converted to the corresponding carbamate by reaction with (R)-(+)-alpha-MBIC and the absolute configurations of the diastereomeric carbamates formed by reaction of (R)- and (S)-NNAL with (R)-(+)-MBIC were thereby assigned. Conversion of metabolically produced NNAL to the same carbamates allowed us to assign the NNAL formed from NNK by rat liver microsomes as (R)-NNAL. The major and minor NNAL-glucuronide diastereomers found in the urine of patas monkeys and humans exposed to NNK were similarly assigned; they were formed from (R)-NNAL and (S)-NNAL, respectively.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14649037	(S)-(−)-α-Methylbenzyl isocyanate		14649-03-7	Price

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