Steric and Electronic Effects, Enantiospecificity, and Reactive Orientation in DNA Binding/Cleaving by Substituted Derivatives of [SalenMnIII]+

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Abstract
Twenty-six derivatives of [SalenMnIII]+ (1) bearing halogen, nitro, amino, ether, alkyl, or aryl substituents on the aromatic rings and/or at the imine positions or containing 1,3-propylene-, 1,2-phenylene-, 1,2-cyclohexane-, or 1,2-diphenylethylenediamine in place of ethylenediamine as the bridging moiety have been synthesized. The DNA binding/cleaving properties of these complexes in the presence of terminal oxidants have been examined using DNA affinity cleaving techniques. Active derivatives produced DNA cleavage from the minor groove at sites containing multiple contiguous A:T base pairs. For aryl-substituted derivatives, DNA cleavage efficiency was found to vary with both the identity and position of attachment of substituents. The precise patterns of cleavage at A:T target sites varied with the position of attachment of substituents, but not with the identity of the substituents. The results suggest that substituents alter specificity through both steric and electronic effects. The 3,3‘-difluoro and -dichloro derivatives produced cleavage patterns that match those of the parent complex, suggesting that the activated form of 1 produces cleavage from an orientation in which the concave edge of the complex faces away from the floor of the DNA minor groove. Bridge modifications yield complexes with reduced DNA cleaving activity relative to 1. DNA cleaving efficiency was found to vary with both the structure and stereochemistry of the bridge. Cleavage efficiency for the complex derived from (R,R)-cyclohexanediamine was 5 times greater than that for the (S,S) enantiomer. Cleavage patterns produced by the enantiomeric complexes at A:T rich target sites were different, demonstrating enantiospecific recognition and cleavage of right-handed double-helical DNA.