Synthesis and cytotoxicity of pyranonaphthoquinone natural product analogues under bioreductive conditions

Bioorg Med Chem. 2013 Dec 15;21(24):7971-80. doi: 10.1016/j.bmc.2013.09.052.


We have synthesised a focused library of derivatives of natural products containing the pyranonaphthoquinone moiety including the first report of such a scaffold with an appended tetrazole functionality. Examples include kalafungin derivatives as well as analogues of nanaomycin and eleutherin. These compounds were assessed for cytotoxic activation by breast cancer cell lines engineered to express the prototypic human one- and two-electron quinone bioreductive enzymes, NADPH: cytochrome P450 oxidoreductase (POR) and

Nad(p)h: quinoneoxidoreductase 1 (NQO1; DT-diaphorase), respectively. Several compounds were observed to be cytotoxic at sub-micromolar level and a pattern of increased aerobic potency was observed in cells over expressing POR. A subset of analogues was assessed under anoxic conditions, where cytotoxicity was reduced, implicating redox cycling as a major mechanism of toxicity. The substrate specificity for reductive enzymes is relevant to the future design of bioreductive prodrugs to treat cancer.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Biological Products / chemical synthesis*
  • Biological Products / chemistry
  • Biological Products / toxicity*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • NADPH-Ferrihemoprotein Reductase / metabolism
  • Naphthoquinones / chemical synthesis
  • Naphthoquinones / chemistry*
  • Naphthoquinones / toxicity*
  • Oxidation-Reduction / drug effects
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Biological Products
  • Naphthoquinones
  • NADPH-Ferrihemoprotein Reductase