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J Org Chem. 2007 Jun 22;72(13):4698-706. Epub 2007 Jun 2.

Synthesis and decomposition of an ester derivative of the procarcinogen and promutagen, PhIP, 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine: unusual nitrenium ion chemistry.

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Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, USA.


The food-derived heterocyclic amine (HCA) carcinogen 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine, PhIP, is often generated in the highest concentration of the HCAs formed during broiling and frying of meat and fish. Although it is considered to be an important contributor to human cancer risk from exposure to HCAs, the chemistry of PhIP metabolites that presumably react with DNA to initiate carcinogenesis has received only cursory attention. We have synthesized the ester derivative N-pivaloxy-2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine, 1b, and investigated its chemistry in aqueous solution. Although 1b was too unstable to isolate, we could characterize it by NMR methods in DMF-d7, a solvent in which it is stable at -40 degrees C. It decomposed rapidly in aqueous solution, but its conjugate acid, 1bH+, is not reactive. The nitrenium ion, 2, was trapped by N(3)(-) to form the unusual tetrazole adduct, 16. In the absence of N3-, the expected hydration products of 2 were not detected, but the reduction product, 12, was detected. Although such products are often taken as evidence of triplet nitrenium ions, the efficient trapping of 2 by N(3)(-) indicates that it is a ground state singlet species. The product 12 appears to be generated by reduction of an initially formed hydration product of 2. An alternative addition-elimination mechanism for the formation of 12 does not fit the available kinetic data. The selectivity of 2, measured as kaz/ks, the ratio of the second-order rate constant for its reaction with N(3)(-) and the first-order rate constant for its reaction with the aqueous solvent, is (2.3 +/- 0.6) x 10(4) M(-1), a value that is in the middle of the range of k(az)/k(s) of 10-10(6) M(-1) observed for nitrenium ions derived from other HCAs. The mutagenicity of aromatic amines (AAs) and HCAs, measured as the log of histidine revertants per nanomole of amine, log m, in Salmonella typhimurium TA 98 and TA 100 correlates with log(k(az)/k(s)) for a wide variety of carbocyclic and heterocyclic amine mutagens including PhIP. Previously developed linear regression models for mutagenicity that include log(k(az)/k(s)) as an independent variable predict log m for PhIP with good accuracy in both TA 98 and TA 100. Quantitative carcinogenicity data are less strongly correlated with log(k(az)/k(s)), so prediction of the carcinogenicity of PhIP and other HCAs or AAs based primarily on log(k(az)/k(s)) is less successful.

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