Synthesis of13C4-labelled oxidized metabolites of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene.
Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that are implicated in causing lung cancer. BaP is a component of tobacco smoke that is transformed enzymatically to active forms that interact with DNA. We reported previously development of a sensitive stable isotope dilution LC/MS method for analysis of BaP metabolites. We now report efficient syntheses of13C4-BaP and the complete set of its13C4-labelled oxidized metabolites needed as internal standards They include the metabolites not involved in carcinogenesis (Group A) and the metabolites implicated in initiation of cancer (Group B). The synthetic approach is novel, entailing use of Pd-catalyzed Suzuki, Sonogashira, and Hartwig cross-coupling reactions combined with PtCl2-catalyzed cyclization of acetylenic compounds. This synthetic method requires fewer steps, employs milder conditions, and product isolation is simpler than conventional methods of PAH synthesis. The syntheses of13C4-BaP and13C4-BaP-8-ol each require only four steps, and the13C-atoms are all introduced in a single step.13C4-BaP-8-ol serves as the synthetic precursor of all the oxidized metabolites of13C-BaP implicated in initiation of cancer. The isotopic purities of the synthetic13C4-BaP metabolites were estimated to be ≥99.9%.
The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, United States.
Anhui
A
Wu
Daiwang
D
Xu
Ding
D
Lu
Trevor M
TM
Penning
Ian A
IA
Blair
Ronald G
RG
Harvey
13C4-Labelled oxidized metabolites of BaP; Benzo[a]pyrene (BaP); Carcinogenic polycyclic aromatic; Enzymatic activation of PAH carcinogens; Synthesis of 13C4-labelled BaP; Synthesis of PAHs via Pd-catalyzed cross-coupling reactions; hydrocarbons (PAHs)