title: Binding of bis-substituted 2-aza-anthracenedione regioisomers to DNA: effects of the relative positioning of the side chains.
abstract: The DNA-binding properties of a series of 2-aza-anthracenedione (benz[g]isoquinoline-5,10-dione) derivatives bearing two 3-dimethylaminopropylamino side chains at different (6,9, 7,9 and 8,9) positions of the planar ring system have been investigated. The affinity for the nucleic acid is dramatically affected by the substitution pattern, the 6,9-regioisomer being substantially more effective than the 7,9- or the 8,9-congeners. This cannot be ascribed to different binding mechanisms, as all compounds are shown to intercalate into the double helix. Instead, the geometry of intercalation into DNA and the site specificity are extensively affected by the substitution pattern. 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. Molecular modeling studies are in agreement with the experimental results. Although the 6,9-regioisomer was remarkably cytotoxic, it stimulated topoisomerase II-mediated cleavage of DNA very poorly. Hence, a different mechanism of DNA damage is probably operating in 2-aza-anthracenediones as the main cell-killing event. Changes in affinity for DNA, intercalation geometry and sequence specificity can explain the different cytotoxic responses exhibited by the test drugs.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sissi
authors.forename: S
authors.initials: S
authors.lastname: Moro
authors.forename: G
authors.initials: G
authors.lastname: Zagotto
authors.forename: M
authors.initials: M
authors.lastname: Ellis
authors.forename: A P
authors.initials: AP
authors.lastname: Krapcho
authors.forename: E
authors.initials: E
authors.lastname: Menta
authors.forename: M
authors.initials: M
authors.lastname: Palumbo
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004278:DNA, Superhelical / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D013053:Spectrophotometry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors
chemical_list: D000880:Anthraquinones; D001372:Aza Compounds; D004278:DNA, Superhelical; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA