Reactivity-selectivity properties of reactions of carcinogenic electrophiles and nucleosides: influence of pH on site selectivity.
6-Chloromethylbenzo[a]pyrene (6-CMBP) labeled with 13C in the chloromethyl group was used as a model for those carcinogens which form essentially free carbocations. Using 13C-NMR to identify products, the selectivity with which this electrophile modifies nucleosides was investigated. At pH 7, guanosine and deoxyguanosine are the most nucleophilic nucleosides toward the carbocation generated by solvolysis of 6-CMBP. Attack at N-7 predominates over attack at N-2. At higher pH, the nucleophilicity of guanosine and deoxyguanosines increases markedly. In addition, the site of modification changes to N-1 with secondary modification at O-6. The pH dependence of the rate of this reaction implicates a group with pK-value approx. 8.7 which was assigned to the hydrogen on N-1. The presence of a methyl group on the N-7 position of guanosine lowers this pK-value to approx. 7.2. Consequently, N7-methylguanosine shows the high nucleophilicity at physiological pH that guanosine has at high pH. These observations lead to the suggestion of a one base : two-site model for chemical carcinogenesis.
D001580:Benzopyrenes; D001665:Binding Sites; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003849:Deoxyguanosine / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008956:Models, Chemical; D009705:Nucleosides / Q000378:metabolism*
D001580:Benzopyrenes; D002273:Carcinogens; D009705:Nucleosides; D006151:Guanosine; C016578:7-methylguanosine; D003849:Deoxyguanosine