title: Mg(2+)-mediated binding of 6-substituted quinolones to DNA: relevance to biological activity.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sissi
authors.forename: M
authors.initials: M
authors.lastname: Andreolli
authors.forename: V
authors.initials: V
authors.lastname: Cecchetti
authors.forename: A
authors.initials: A
authors.lastname: Fravolini
authors.forename: B
authors.initials: B
authors.lastname: Gatto
authors.forename: M
authors.initials: M
authors.lastname: Palumbo
mesh_terms: D001665:Binding Sites; D004277:DNA, Single-Stranded / Q000378:metabolism*; D005470:Fluorometry; D008274:Magnesium / Q000378:metabolism*; D015363:Quinolones / Q000378:metabolism*
chemical_list: D004277:DNA, Single-Stranded; D015363:Quinolones; D008274:Magnesium