title: Selectivity of purine alkylation by a quinone methide. Kinetic or thermodynamic control?
abstract: The alkylation reaction of 9-methyladenine and 9-methylguanine (as prototype substrates of deoxy-adenosine and -guanosine), by the parent o-quinone methide (o-QM), has been investigated in the gas phase and in aqueous solution, using density functional theory at the B3LYP/6-311+G(d,p) level. The effect of the medium on the reactivity, and on the stability of the resulting adducts, has been investigated by using the C-PCM solvation model to assess which adduct arises from the kinetically favorable path, or from an equilibrating process. The calculations indicate that the most nucleophilic site of the methyl-substituted nucleobases in the gas phase is the guanine oxygen atom (O(6)) (DeltaG()(gas) = 5.6 kcal mol(-)(1)), followed by the adenine N1 (DeltaG)(gas) = 10.3 kcal mol(-)(1)), while other centers exhibit a substantially lower nucleophilicity. The bulk effect of water as a solvent is the dramatic reduction of the nucleophilicity of both 9-methyladenine N1 (DeltaG)(solv) = 14.5 kcal mol(-)(1)) and 9-methylguanine O(6) (DeltaG)(solv) = 17.0 kcal mol(-)(1)). As a result there is a reversal of the nucleophilicity order of the purine bases. While O(6) and N7 nucleophilic centers of 9-methylguanine compete almost on the same footing, the reactivity gap between N1 and N7 of 9-methyladenine in solution is highly reduced. Regarding product stability, calculations predict that only two of the adducts of o-QM with 9-methyladenine, those at NH(2) and N1 positions, are lower in energy than reactants, both in the gas phase and in water. However, the adduct at N1 can easily dissociate in water. The adducts arising from the covalent modification of 9-methylguanine are largely more stable than reactants in the gas phase, but their stability is markedly reduced in water. In particular, the oxygen alkylation adduct becomes slightly unstable in water (DeltaG(solv) = +1.4 kcal mol(-)(1)), and the N7 alkylation product remains only moderately more stable than free reactants (DeltaG(solv) = -2.8 kcal mol(-)(1)). Our data show that site alkylations at the adenine N1 and the guanine O(6) and N7 in water are the result of kinetically controlled processes and that the selective modification of the exo-amino groups of guanine N2 and adenine N6 are generated by thermodynamic equilibrations. The ability of o-QM to form several metastable adducts with purine nucleobases (at guanine N7 and O(2), and adenine N1) in water suggests that the above adducts may act as o-QM carriers.
authors.affiliation: Dipartimento di Chimica Organica, Università di Pavia, Viale Taramelli 10, 27100 Pavia, Italy. mauro.freccero@unipv.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
authors.forename: Remo
authors.initials: R
authors.lastname: Gandolfi
authors.forename: Mirko
authors.initials: M
authors.lastname: Sarzi-Amadè
mesh_terms: D000478:Alkylation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004734:Energy Metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D007202:Indicators and Reagents; D045563:Indolequinones / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011687:Purines / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D007202:Indicators and Reagents; D045563:Indolequinones; D011687:Purines; C068040:quinone methide; C116701:9-methylguanine; D006147:Guanine