On the reaction of mutagenic aflatoxin B 1 oxide and benz[ a]pyrene diol oxide with guanine residue in DNA double helix

Abstract

Theoretical calculation was performed to study the binding mechanism of intercalators to deoxyribonucleic acid (DNA) base pairs. The structures of intercalating complexes and ligand–DNA adducts of mutagenic aflatoxin B 1 8,9-oxide ( 1) and benz[ a]pyrene diol oxide ( 2) and the reactivity for S N2 type nucleophilic oxirane ring opening for 2 were investigated. Calculation clarified the following points: 1. The atomic contacts between two reaction sites (nucleophilic N2 or N7 nitrogen lone pair of guanine residue in DNA base pairs and electrophilic carbon of three-membered oxirane ring in mutagenic 1 and 2) are considerably short, suggesting that intercalation makes two reaction sites closer and consequently promotes the covalent binding of mutagens to guanine base. 2. In the adducts of 1 and 2 with DNA double helix, large planar coumarin ring of 1 exists in the major groove of double helix and planar aromatic ring system of 2 in minor groove of it. The regularly layered structure of B type DNA double helix is not distorted in the adduct of 1, however, the double helix is considerably distorted in the adduct of 2. 3. Two mutagens probably intercalate into DNA base pairs and make stable complexes which are followed by transition structures (TSs) for covalent binding. Judging from the activation energy (Δ E ≠) estimated to be 47.7 kcal/mol, the reactivity for covalent binding is considerably low, implying that intercalation must play an important role as precedent phenomena to covalent binding between bases and intercalators. Calculation suggests that the reactivity for S N2 type nucleophilic reaction itself (the stability of TS for covalent binding) is not so high, and therefore, the potency for mutagenesis might be attributing to the formation of stable (and consequently) long standing intercalating complex and stable ligand–DNA adduct.