Affiliation:
1. Department of Chemistry Beckman Institute for Advanced Science and Technology Cancer Center at Illinois University of Illinois at Urbana-Champaign Urbana Illinois 61801 United States
Abstract
AbstractFluoroquinolones such as levofloxacin and ciprofloxacin are potent antibiotics prescribed to treat various bacterial infections. Recent studies have also identified prominent examples as promising anti‐cancer agents. However, significant off‐target effects observed in human patients have precluded their wide‐spread clinical use. For instance, upon systemic administration, overt toxicity toward eukaryotic organelles (i. e., mitochondria) can result to the destruction of healthy tissue. Moreover, fluoroquinolones feature a β‐ketoacid motif which binds to and strips magnesium ions from cartilage, leading to rupture of the Achilles tendon. In this study, we have masked the β‐ketoacid of levofloxacin and ciprofloxacin (as well as two quinolones) with a nitroreductase (NTR)‐responsive warhead appended through a new self‐immolative prodrug linker. The resulting β‐ketoester functional group was found to be remarkably resistant toward spontaneous hydrolysis, esterase activity, as well as other ester‐cleaving enzymatic systems. Further testing also reveal no cross‐reactivity against commonly encountered biologically relevant analytes (e. g., ROS and thiols). Importantly, we demonstrate that upon esterification, the binding toward magnesium ions was attenuated based on an in vitro fluorescent competition assay with the unmodified parent drug.
Funder
Camille and Henry Dreyfus Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Drug Discovery,Biochemistry,Catalysis
Reference51 articles.
1. ‘Quinolones: A Comprehensive Review’;Oliphant C. M.;Am. Fam. Physician,2002
2. Quinolone antibiotics
3. The New Fluoroquinolones: A Critical Review
4. Fluoroquinolone antibiotics and adverse events
5. ‘The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know?’;Kim G. K.;J. Clin. Aesthet. Dermatol.,2010