The Relationship between the Chemical Structures of Dihydropyrazine Derivatives and DNA Strand-Breakage Activity

Abstract

Dihydropyrazine, a compound derived from sugars, possesses DNA strand-breakage activity. The relationship between the activity as assayed using pBR 322 ccc-DNA and the chemical structures of derivatives of dihydropyrazine (DHPs) has been investigated. The addition of Cu²⁺ enhanced the activity remarkably. The introduction of a methyl or phenyl group onto the DHP ring or a cyclohexyl group fused onto the DHP ring also increased the activity. These properties indicated that the activity was due to the facility of electron release from the DHP ring, followed by radical generation. The determination of ionization potential and electrostatic potential values, and bond dissociation energy via semi-empirical MO calculations suggested strongly that the activity is induced by a DHP ring structure that contains a configuration suitable for hyperconjugation.