Mg2+-mediated binding of 6-substituted quinolones to DNA: Relevance to biological activity

The interaction of a number of novel 6-substituted quinolone derivatives with DNA in the presence/absence of magnesium ions has been investigated by ¯uorometric 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+ con- centration. From titrations at di€erent [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 quino- lones (IC50), which con®rms that DNA-anity of the quinolone, modulated by Mg2+, plays an important role in poi- soning the cleavable gyrase±DNA complex and, consequently, in eliciting antibacterial activity in this family of drugs. The results obtained with di€erent 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.