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 in their DNA-binding properties. 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, as well as the site specificity, are extensively affected by the substitution pattern. The site preference is, in fact, C-A (or A-C) for the 6,9-regioisomer, whereas it is T-A (or A-T) 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 very poorly topoisomerase II-mediated cleavage of DNA. 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, in intercalation geometry and in sequence-specificity can explain the different cytotoxic responses exhibited by the test drugs.

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

SISSI, CLAUDIA;MORO, STEFANO;ZAGOTTO, GIUSEPPE;PALUMBO, MANLIO
1999

Abstract

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 in their DNA-binding properties. 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, as well as the site specificity, are extensively affected by the substitution pattern. The site preference is, in fact, C-A (or A-C) for the 6,9-regioisomer, whereas it is T-A (or A-T) 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 very poorly topoisomerase II-mediated cleavage of DNA. 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, in intercalation geometry and in sequence-specificity can explain the different cytotoxic responses exhibited by the test drugs.
1999
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2473183
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 10
social impact