Targeting Abasic Sites in DNA by Aminoalkyl‐Substituted Carboxamidoacridizinium Derivatives and Acridizinium–Adenine Conjugates

Abstract

Abstract Two isomeric acridizinium–adenine conjugates, along with three model compounds (i.e. two 9‐( N ‐alkylcarboxamido)acridizinium salts and one 9‐{ N ‐[(dimethylamino)alkyl]carboxamido}acridizinium salt) were prepared from the corresponding carboxyacridizinium salts. The interaction of these compounds with calf thymus DNA was studied by spectrophotometric and viscosimetric titrations, LD spectroscopy, and thermal DNA denaturation experiments. Both of the acridizinium–adenine conjugates and the N ‐alkylcarboxamides intercalate into calf thymus DNA with moderate affinity [ K ≈ 10 4 M –1 (DNA concentration in bp)]. In contrast, the N ‐[3‐(dimethylamino)propyl]‐substituted carboxamide exhibits a significantly higher binding constant under identical conditions ( K ≈ 10 5 M –1 ). The association of the acridizinium derivatives with abasic‐site containing DNA was assessed by thermal denaturation experiments with synthetic double‐stranded oligonucleotides, which contained one (TX) or no abasic site (TA). The acridizinium–adenine conjugates stabilize the DNA with the abasic position slightly more than they do the regular duplex, as indicated by the difference of the induced melting‐temperature shifts between the TX and TA duplexes (ΔΔ T m ≈ 4 °C) at a ligand/DNA ratio r of 0.5. Most notably, a significantly more efficient stabilization (ΔΔ T m = 9.6 °C) of the abasic duplex is achieved by theaminoalkyl derivative, namely 9‐{ N ‐[3‐(dimethylamino)propyl]carboxamido}acridizinium salt, which does not carry an adenine substituent. These results indicate that the design of abasic‐site‐targeting ligands must not necessarily involve the attachment of a nucleic acid base to the DNA intercalator.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)