Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone - A novel class of compounds with potent activity against acute myeloid leukemia cells

Bioorg Med Chem Lett. 2017 Jan 1;27(1):6-10. doi: 10.1016/j.bmcl.2016.11.045. Epub 2016 Nov 17.

Abstract

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.

Keywords: Acute myeloid leukemia; Aziridine; DNA damage; Naphthoquinone; Reactive oxygen species.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Breaks, Double-Stranded / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred NOD
  • Molecular Structure
  • Naphthoquinones / chemical synthesis
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Naphthoquinones
  • Reactive Oxygen Species