Binding of bis-substituted 2-aza-anthracenedione regioisomers to DNA: effects of the relative positioning of the side chains

The DNA-binding properties of a series of 2-aza-anthracenedione (benz[g]iso quinoline-5,10-dione) derivatives bearing two 3-dimethylaminopropylamino si de chains at different (6,9, 7,9 and 8,9) positions of the planar ring syst em have been investigated, The affinity for the nucleic acid is dramaticall y affected by the substitution pattern, the 6,9-regioisomer being substanti ally more effective than the 7,9- or the 8,9-congeners. This cannot be ascr ibed to different binding mechanisms, as all compounds are shown to interca late into the double helix. Instead, the geometry of intercalation into DNA and the site specificity are extensively affected by the substitution patt ern, The site preference is CA (or AC) for the 6,9-regioisomer, whereas it is TA (or AT) for the 8,9-congener, the 7,9-analogue lying in between. Mole cular modeling studies are in agreement with the experimental results. Alth ough the 6,9-regioisomer was remarkably cytotoxic, it stimulated topoisomer ase II-mediated cleavage of DNA very poorly. Hence, a different mechanism o f DNA damage is probably operating in 2-aza-anthracenediones as the main ce ll-killing event, Changes in affinity for DNA, intercalation geometry and s equence specificity can explain the different cytotoxic responses exhibited by the test drugs.