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Mg(2+)-mediated binding of 6-substituted quinolones to DNA: relevance to biological activity.

Authors
  • Sissi, C
  • Andreolli, M
  • Cecchetti, V
  • Fravolini, A
  • Gatto, B
  • Palumbo, M
Type
Published Article
Journal
Bioorganic & Medicinal Chemistry
Publisher
Elsevier
Publication Date
Sep 01, 1998
Volume
6
Issue
9
Pages
1555–1561
Identifiers
PMID: 9801827
Source
Medline
License
Unknown

Abstract

The interaction of a number of novel 6-substituted quinolone derivatives with DNA in the presence/absence of magnesium ions has been investigated by fluorometric techniques. The drug-single-stranded nucleic acid interaction is invariantly mediated by the metal ion. In all cases optimal complex formation is found at physiological Mg2+ concentration. From titrations at different [Mg2+] the binding constant for the ternary drug-DNA-Mg2+ complex (KT) has been evaluated. Interestingly, a good relationship is found between KT and gyrase poisoning activity of the test quinolones (IC50), which confirms that DNA-affinity of the quinolone, modulated by Mg2+, plays an important role in poisoning the cleavable gyrase-DNA complex and, consequently, in eliciting antibacterial activity in this family of drugs. The results obtained with different 6-substituted compounds supports the idea that position 6 of the drug, besides playing a pharmacokinetic role, is involved in recognition of the enzyme pocket. Our data do not support a mechanism of action based upon quinolone intercalation into B-DNA.

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