DNA interaction of bromomethyl-substituted acridines

Abstract

A series of acridines with bifunctional substituents was synthesized with the dual properties of DNA alkylation and intercalation. 4,5-Bis(bromomethyl)acridine (1) was previously reported to crosslink and intercalate with DNA. In this study, 1,8-bis(bromomethyl)acridine (2) and 2,7-bis(bromomethyl)acridine (3), monofunctional 2-(bromomethyl)-7-methylacridine (4) and 2,7-dimethylacridine (5) were synthesized, and their crosslinking and intercalative activities were investigated to assess the reactivity of bromomethyl acridines with DNA. Interstrand crosslinking activity was similar among the three bis(bromomethyl)acridines. The acridines exhibited intercalation activity for calf thymus DNA as follows: 3 > 4 > 2 = 1 >>> 5. Intracellular DNA-crosslinking and DNA-intercalating activities were evaluated using the Ames assay. 4 was mutagenic in Salmonella typhimurium TA100 and TA98, indicating that the bromomethyl group alkylated DNA bases. All three bis(bromomethyl)acridines were mutagenic in S. typhimurium TA92 and TA94, which can detect intracellular crosslinking DNA damage, whereas 5 was not mutagenic in these strains. The results showed that the bis(bromomethyl)acridines crosslinked DNA and intercalated between DNA bases, and 3 exhibited the highest crosslinking and intercalating activity.