Preparation of pyridine-N-glucuronides of tobacco-specific nitrosamines

Chem Res Toxicol. 2001 May;14(5):555-61. doi: 10.1021/tx000262e.

Abstract

Nicotine and cotinine are metabolized to pyridine-N-glucuronides in humans. This suggests that the analogous metabolites of the carcinogenic nicotine-related nitrosamines N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) should also be formed in people exposed to these compounds via tobacco products. We describe the synthesis of the appropriate pyridine-N-glucuronides: pyridyl-N-beta-D-glucopyranuronosyl-N'-nitrosonornicotinium inner salt (NNN-N-Gluc, 8), 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanonium inner salt (NNK-N-Gluc, 9), and 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanolonium inner salt (NNAL-N-Gluc, 10). The starting material, methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate (1), is prepared in two steps from glucuronolactone. Reactions of 1 with racemic NNN (2), NNK (3), or racemic NNAL (4) are carried out with no solvent and the crude products are deprotected by treatment with base, giving the desired N-glucuronides 8-10 in 5-7% overall yield after HPLC purification. The N-glucuronides were characterized by (1)H NMR, including COSY and NOESY spectra, and by MS and MS/MS. NNN-N-Gluc exists as a 52:48 ratio of (E)- and (Z)-rotamers, which were partially separated by HPLC. This ratio was surprisingly similar to the (E):(Z) ratio for NNN itself suggesting hydrogen bonding of the (Z)-nitroso oxygen atom to the 2' '-hydroxyl group of the glucuronide moiety. Partial HPLC separations of the (E)- and (Z)-rotamers of NNK-N-Gluc and the (E)- and (Z)-rotamers as well as the (R)- and (S)-diastereomers of NNAL-N-Gluc were also achieved. The standards prepared in this study as well as the HPLC conditions developed for their separation will be important for analysis of these compounds in human urine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromatography, High Pressure Liquid / methods
  • Glucuronides / chemical synthesis*
  • Glucuronides / standards
  • Magnetic Resonance Spectroscopy / methods
  • Nicotiana / chemistry
  • Nitrosamines / chemistry*
  • Plants, Toxic
  • Pyridines / chemical synthesis*
  • Pyridines / standards

Substances

  • Glucuronides
  • Nitrosamines
  • Pyridines
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol
  • N'-nitrosonornicotine