Mg(2+)-mediated binding of 6-substituted quinolones to DNA: relevance to biological activity |
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Authors: | C Sissi M Andreolli V Cecchetti A Fravolini B Gatto M Palumbo |
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Affiliation: | Department of Pharmaceutical Sciences, University of Padova, Italy. |
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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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