Dynamic Intramolecular Cap for Preserving Metallodrug Integrity─A Case of Catalytic Fluoroquinolones.

A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the cyclen moiety was designed and synthesized to investigate their potential for overcoming the general issue of "metallodrug vulnerability" under physiological conditions. The Cu(II) and Co(III) complexes of the new designer compounds were synthesized, and their potential to operate a dynamic, intramolecular cap with DNase activity was explored. The lead Co(III)-cyclen-ciprofloxacin conjugate showed excellent hydrolytic DNase activity, which was retained in the presence of strong endogenous chelators and exhibited enhanced antibacterial activity relative to the metal-free ligand (in the absence of any adjuvants), thereby demonstrating a "proof of concept" and , respectively, for the dynamic cap hypothesis.

Toward Catalytic Antibiotics: Redesign of Fluoroquinolones to Catalytically Fragment Chromosomal DNA.

A library of ciprofloxacin-nuclease conjugates was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the new designer compounds (i) showed excellent hydrolytic and oxidative DNase activity, (ii) showed good antibacterial activity against both Gram-negative and Gram-positive bacteria, and (iii) proved to be highly potent bacterial DNA gyrase inhibitors via a mechanism that involves stabilization of the fluoroquinolone-topoisomerase-DNA ternary complex. Furthermore, the Cu(II) complexes of two of the new designer compounds were shown to fragment supercoiled plasmid DNA into linear DNA in the presence of DNA gyrase, demonstrating a "proof of concept" .