Abstract
The potential anticancer effect of fluoroquinolone antibiotics has been recently unveiled and related to their ability to interfere with DNA topoisomerase II. We herein envisioned the design and synthesis of novel Ciprofloxacin and Norfloxacin nitric oxide (NO) photo-donor hybrids to explore the potential synergistic antitumor effect exerted by the fluoroquinolone scaffold and NO eventually produced upon light irradiation. Anticancer activity, evaluated on a panel of tumor cell lines, showed encouraging results with IC50 values in the low micromolar range. Some compounds displayed intense antiproliferative activity on triple-negative and doxorubicin-resistant breast cancer cell lines, paving the way for their potential use to treat aggressive, refractory and multidrug-resistant breast cancer. No significant additive effect was observed on PC3 and DU145 cells following NO release. Conversely, antimicrobial photodynamic experiments on both Gram-negative and Gram-positive microorganisms displayed a significant killing rate in Staphylococcus aureus, accounting for their potential effectiveness as selective antimicrobial photosensitizers.
Highlights
Since their early discovery as byproducts of chloroquine synthesis,[1] quinolones have represented one of the most important classes of antibiotics for urinary and respiratory infection treatment.[2−4] Quinolones exert their bactericidal activity by interfering with DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria.[5]Both enzymes belong to the topoisomerase family, which plays an essential role in the regulation of the DNA topological state, in DNA replication, and in the condensation and segregation of chromosomes.[6,7] In the presence of quinolone, the enzyme forms a DNA/enzyme/drug ternary complex that perturbsDNA replication, leading to bacterial death or eukaryotic cell apoptosis
Methyl esters 3a and 3b were synthesized in two steps, including a Fisher esterification between Cip or Nor with refluxing methanol, and p-toluenesulfonic acid (22 h) to afford esters 2a and 2b that were subsequently reacted with 4-fluorocharacteristic peaks at 400 and 450 nm, respectively
Docking studies confirmed that these novel chemical entities effectively bind to both bacterial and human topoisomerases, with better calculated free binding energies with respect to the parent compounds
Summary
Since their early discovery as byproducts of chloroquine synthesis,[1] quinolones have represented one of the most important classes of antibiotics for urinary and respiratory infection treatment.[2−4] Quinolones exert their bactericidal activity by interfering with DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria.[5]Both enzymes belong to the topoisomerase family, which plays an essential role in the regulation of the DNA topological state, in DNA replication, and in the condensation and segregation of chromosomes.[6,7] In the presence of quinolone, the enzyme forms a DNA/enzyme/drug ternary complex that perturbsDNA replication, leading to bacterial death or eukaryotic cell apoptosis. Since their early discovery as byproducts of chloroquine synthesis,[1] quinolones have represented one of the most important classes of antibiotics for urinary and respiratory infection treatment.[2−4] Quinolones exert their bactericidal activity by interfering with DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria.[5] Both enzymes belong to the topoisomerase family, which plays an essential role in the regulation of the DNA topological state, in DNA replication, and in the condensation and segregation of chromosomes.[6,7] In the presence of quinolone, the enzyme forms a DNA/enzyme/drug ternary complex that perturbs. To expand their spectrum of action and improve pharmacokinetics, a saturated heterocyclic ring containing an amine function was introduced at the 7-position from the second-generation fluoroquinolones.[10]
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