Design, synthesis, and biological evaluation of novel ciprofloxacin derivatives as potential anticancer agents targeting topoisomerase II enzyme

J Enzyme Inhib Med Chem. 2023 Dec;38(1):118-137. doi: 10.1080/14756366.2022.2136172.

Abstract

A series of novel ciprofloxacin (CP) derivatives substituted at the N-4 position with biologically active moieties were designed and synthesised. 14 compounds were 1.02- to 8.66-fold more potent than doxorubicin against T-24 cancer cells. Ten compounds were 1.2- to 7.1-fold more potent than doxorubicin against PC-3 cancer cells. The most potent compounds 6, 7a, 7b, 8a, 9a, and 10c showed significant Topo II inhibitory activity (83-90% at 100 μM concentration). Compounds 6, 8a, and 10c were 1.01- to 2.32-fold more potent than doxorubicin. Compounds 6 and 8a induced apoptosis in T-24 (16.8- and 20.1-fold, respectively compared to control). This evidence was supported by an increase in the level of apoptotic caspase-3 (5.23- and 7.6-fold, sequentially). Both compounds arrested the cell cycle in the S phase in T-24 cancer cells while in PC-3 cancer cells the two compounds arrested the cell cycle in the G1 phase. Molecular docking simulations of compounds 6 and 8a into the Topo II active site rationalised their remarkable Topo II inhibitory activity.

Keywords: Design; anti-proliferative activity; ciprofloxacin; synthesis; topoisomerase II.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Cell Line, Tumor
  • Cell Proliferation
  • Ciprofloxacin / chemistry
  • Ciprofloxacin / pharmacology
  • DNA Topoisomerases, Type II* / metabolism
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Drug Screening Assays, Antitumor
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Ciprofloxacin
  • DNA Topoisomerases, Type II
  • Doxorubicin