Structural studies ofO6-methyldeoxyguanosine and related compounds: a promutagenic DNA lesion by methylating carcinogens

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Abstract
O6-Methylation of guanine residues in DNA can induce mutations by formation of base mispairing due to the daprotonation of N(l). The electronic, geometric and conformational properties of three N(9)-Substituted O6-methylguanine derivatives, O6-methyldeoxyguanosine (O6mdGuo), O6-methylguanosine (O6 mGuo) and O6, 9-dimethylguanine (O6 mGua), were investigated by X-ray and/or MMR studies. O6 mdGuo crystallizes in the monoclinico space group P21 with cell parameters a=5.267(1), b=19.109(2), c=12.330(2) A, β=92.45(1)°, V=1239.8(3) A3, Z=4 (two nucleosides per asymmetric unit), and O6mGua in the monoclinic space group P21/n with cell parameters a=10.729(2), b=7.640(l), c=10.216(l) A, β=92.17(2)•, V=836.7(2) A3, Z=4. The geometry and conformation of O6-methylguanine moieties observed in both crystals are very similar. Furthermore, the molecular dimensions of the O6 methylguanine residue resemble more closely those of adenine than those of guanine. The methoxy group is coplanar with the purine ring, the methyl group being cis to N(l). The conformation of O6 -methylguanine nucleosides is variable. The glycosidic conformation of O6mdGuo is anti for molecule (a) and high-anti for molecule (b) in the crystal, while that of 0 mGuo is syn [Parthasarathy, R & Fridey, S. M. (1986) Carcinogenesis 7, 221–227], The sugar ring pucker of O6mdGuo is C(2')-endo for molecule (a) and C(l')-exo for molecule (b). The C(4')-C(5I) exocyclic bond conformation in O6 mdGuo is gauche− for molecule (a) but trans for molecule (b), in contrast with gauche+ for O6mGuo. The hydrogen bonds exhibited by O6 -methylguanine derivatives differ from those in guanine derivatives; the amino N(2) and ring N(3) and N(7) atoms of O6 -methylguanine residues are involved in hydrogen bonding.1 H-NMR data for O6mdGuo and O6mGuo reveal the predominance of a C(2')-endo type sugar puckering. In O6mdGuo, however, a contribution of a C(l')-exo sugar puckering is significant. The NOE data also indicate that O6mdGuo molecules exist with nearly equal population for anti (including high anti) and eyn glycosidic conformations. These observations and their biological implications are discussed.