- Synthesis of a new isomer of creatinine and its use in the preparation of the food mutagen 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PHIP)
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Base-induced cyclization of N′-cyanomethyl-N′-methylurea gives 1-methyl-4-amino-imidazol-2-one, this in turn is condensed with 3-hydroxy-2-phenylacrolein to yield an imidazo[4,5-b]pyridine which is converted into 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PHIP).
- Bergman, Jan
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- Indole: A Promising Scavenging Agent for Methylglyoxal and Related Carbonyls in Tryptophan Containing Maillard Model Systems
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In situ generation of efficient carbonyl trapping agents from amino acids during food processing can be considered a useful approach to control the accumulation of harmful Maillard reaction products in food. Tryptophan is one such amino acid that can be used to generate carbonyl trapping agents. Indole, the main thermal degradation product of tryptophan, is known to react with simple aldehydes through electrophilic aromatic substitution type reactions mainly at carbon positions 2 and 3 in addition to the ring nitrogen. The ability of indole to scavenge three moles of reactive aldehydes per mole of indole such as formaldehyde, methylglyoxal, and phenylacetaldehyde was investigated using model systems containing tryptophan or indole. The model systems were either (a) heated in an aqueous solution in stainless steel reactors at specified time and temperatures and analyzed by qTOF-MS/MS or (b) directly pyrolyzed and analyzed by GC/MS using isotope labeling technique. Unlike the other aldehydes, the initial alcohol formed with phenylacetaldehyde was able to dehydrate and form an stable conjugated system with the indole. In general, indole was able to capture three moles of paraformaldehyde, three moles of methylglyoxal and three moles of phenylacetaldehyde and suppress the formation of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) generated in a model system.
- Ghassem Zadeh, Raheleh,Yaylayan, Varoujan
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- A test of the mutagenicity of cooked meats in vivo
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There is a correlation between intestinal cancer and diets high in meat, so fried beef, chicken, lamb, pork and fish were tested for their ability to induce mutations in the small intestine of mice. The mice were bred to be heterozygous at the Dlb-1 locus so that loss of the dominant Dlb-1b allele by mutation could be detected. Mice were fed the AIN-76A diet (which contains 50% of the calories in the form of sucrose) or an isocaloric diet in which the sucrose was replaced by meat or fish, for 5 or 9 weeks. Manifestation of mutants requires ~1 week in this system, so this corresponds to an effective exposure of 4 and 8 weeks, respectively. There was no significant difference in the weights of animals on the different diets, and no difference in mutant frequency. Several food mutagens were present, but at low levels. These results, when considered in the light of tests of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and amino(α)carboline at much higher doses (Zhang,X.-B., Tao,K.S., Urlando,C., Shaver-Walker,P. and Heddle,J.A. (1996) Mutagenesis, 11, 43-48), indicate that there is no highly mutagenic compound missed by previous testing with bacterial assays and that mixtures of heterocyclic amines at low levels do not show great synergy.
- Heddle, John A.,Knize, Mark G.,Dawod, David,Zhang, Xue-Bin
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- Cross-coupling reaction of 2-halo1-methyl-1H-imidazo[4,5-b]pyridine offers a new synthetic route to mutagenic heterocyclic amine-PHIP and DMIP
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A modified synthetic approach to the synthesis of heterocyclic food mutagens, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PHIP) and 2-amino-1,6-dimethylimidazo[4,5-b]pyridine (DMIP) is reported. This route highlights an optimized palladium catalysed Buchwald cross-coupling of 2-halo-1-methyl-imidazo[4,5-b]pyridine with benzophenoneimine followed by acidic hydrolysis to yield compound 7. Using finely tailored conditions, Suzuki cross-coupling reactions with highly efficient catalytic systems were performed as the final step on 8 to introduce the aryl group and methyl group on the heterocyclic core.
- Sajith, Ayyiliath M.,Muralidharan, Arayambath,Karuvalam, Ranjith P.,Haridas, Karickal R.
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supporting information
p. 361 - 364
(2013/07/26)
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- Synthesis and mutagenic potency of structural isomers of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
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(Chemical Equation Presented) Synthesis of 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), three structural isomers, and two desphenyl PhIP congeners has been carried out. Mutagenic potency was evaluated using S. typhimurium strain TA98 in the Ames test. Mutagenic potency increased in relation to structural features in these heterocyclic amines that allow extended resonance between the phenyl and imidazo[4,5-b]pyridine N2-amino substituents. By contrast, PhIP isomers, whose substitution disallows involvement of the phenyl group in their ammoimidazo resonance hybrids, and desphenyl congeners were from 86- to 234-fold less mutagenic than PhIP.
- Chrisman,Knize,Tanga
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experimental part
p. 1641 - 1649
(2009/08/09)
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- 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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(Chemical Equation Presented) 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°C. It decomposed rapidly in aqueous solution, but its conjugate acid, 1bH+, is not reactive. The nitrenium ion, 2, was trapped by N3- 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 N3- 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/k s, the ratio of the second-order rate constant for its reaction with N3- and the first-order rate constant for its reaction with the aqueous solvent, is (2.3 ± 0.6) × 104 M -1, a value that is in the middle of the range of k az/ks of 10-106 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(kaz/ks) for a wide variety of carbocyclic and heterocyclic amine mutagens including PhIP. Previously developed linear regression models for mutagenicity that include log(kaz/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(kaz/ks), so prediction of the carcinogenicity of PhIP and other HCAs or AAs based primarily on log(k az/ks) is less successful.
- Nguyen, Thach-Mien,Novak, Michael
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p. 4698 - 4706
(2008/02/10)
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- Synthesis of novel 2-aminoimidazo[4,5-b]pyridines, including the thieno analogue of the cooked-food mutagen IFP
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Eight new compounds, including three new ring systems obtained via the Friedlunder condensation of ortto-aminothiophenecarbaldehydes 11, 21 and 24 with creatinine (8), are reported. The condensation afforded 1, which is the thieno analogue of the cooked-food mutagen IFP (2-amino-1,6-dimethylfuro[2,3-e] imidazo[4,5-b]pyridine), and the benzothieno[2,3-e]- and benzothieno[3,2-e] imidazo[4,5-b]pyridines 2 and 3. Attempts to condense 11 with isocreatinine (12) were unsuccesful. Desulfurization of 3 gave the known cooked-food carcinogen PhIP, The 2-nitro (4) and 2-hydroxy (5) derivatives of 3 are reported. The related 2-amino-1-methyl-imidazo[4,5-b]benzothiophene (25) was synthesized by a different route. Fully assigned 1H and 13C nmr data of all new compounds are reported.
- Bjoerk, Malin,Grivas, Spiros
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p. 101 - 109
(2007/10/03)
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- An easy photochemical approach to the synthesis of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
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Mutations induced by substances formed during food cooking are a field of growing interest; for a better comprehension of the mechanism of action of these carcinogens, simple routes to their synthesis are needed. In this letter we describe an easy method for 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) synthesis, starling from the commercially available 2,3- diaminopyridine 1 via the 2-amino-3-methylamino-5-phenylpyridine 5 formation. The key step of this approach is the one pot synthesis of 5 performed by photolysis of 2-amino-5-iodo-3-(N-methyl-N-tosylamino)pyridine 4 to obtain simultaneous phenylation and tosyl group removal. Compound 5 was then used as an intermediate to obtain the 1-methyl 6-phenylimidazo[4,5-b]pylidine 6 which was aminated to afford PhIP in good overall yields.
- Bavetta, Fabio S.,Caronna, Tullio,Pregnolato, Massimo,Terreni, Marco
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p. 7793 - 7796
(2007/10/03)
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- Friedlaender synthesis of the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
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2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine has been prepared in 26% yield from 3-amino-2-phenylpropenal and creatinine which were heated with N,O-bis(trimethylsilyl)acetamide at 120 degrees C for 2 h. Under certain other conditions, the main product was a pyrimidine derivative.
- Lindstroem
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p. 361 - 363
(2007/10/02)
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- Synthetic Routes to Nitroamino Precursors of the Food Carcinogen 2-Amino-1-methyl-6-phenyl-1H-imidazopyridine and its 3-Methyl Isomer via Pd(0)-Catalysed Arylation
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The synthesis of the novel key intermediates 3-methylamino-2-nitro- and 2-methylamino-3-nitro-5-phenylpyridine, and some of their derivatives substituted in the benzene ring, from 5-bromonicotinic acid, 3-bromo-5-methoxypyridine, 2-chloro-3-nitropyridine, 2-amino-5-bromopyridine or 5-bromo-2-methoxypyridine is described.Palladium(0)-mediated arylation of bromopyridines with areneboronic acids was an essential step in the syntheses.
- Linstroem, Stefan,Eriksson, Mikael,Grivas, Spiros
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p. 805 - 812
(2007/10/02)
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- THE SYNTHESIS OF THE COOKED-BEEF MUTAGEN 2-AMINO-1-METHYL-6-PHENYLIMIDAZOPYRIDINE AND ITS 3-METHYL ISOMER
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2-Amino-1-methyl-6-phenylimidazopyridine, a mutagenic compound newly isolated from cooked beef, and its 3-methyl isomer have been synthesized.The spectroscopic data and the mutagenicity of the isomers are compared.
- Knize, Mark G.,Felton, James S.
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p. 1815 - 1819
(2007/10/02)
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