Indirubin 3'-(O-oxiran-2-ylmethyl)oxime: a novel anticancer agent

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1403-6. doi: 10.1016/j.bmcl.2015.02.053. Epub 2015 Feb 28.

Abstract

Indirubin is a potent inhibitor of cell cycle-related protein kinases by binding to the ATP-binding site and thus is a promising compound for development as an antitumor drug. We prepared indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind), in which the ATP-binding site orientated part was attached by non-specific alkylating group. The IC50 value of Epox/Ind at 1.7 μM in HepG2 cells is comparable to that of cisplatin (4.0 μM). Furthermore, Epox/Ind was shown to be metabolized by a HepG2 cell lysate into indirubin 3'-(O-2,3-dihydroxypropyl)oxime (E804), the sole extractable metabolite. The lower toxicity of this metabolite may explain the lack of cytotoxicity of 1 μM Epox/Ind observed in HepG2 cells beyond an initial loss of viability in the first 24h of treatment.

Keywords: Adduct; Anticancer agent; Epoxide; Indirubin; Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Hep G2 Cells
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Oximes / chemical synthesis
  • Oximes / chemistry
  • Oximes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Indoles
  • Oximes
  • indirubin 3'-(O-oxiran-2-ylmethyl)oxime