Design and synthesis of novel hydroxyanthraquinone nitrogen mustard derivatives as potential anticancer agents via a bioisostere approach

Eur J Med Chem. 2015 Sep 18:102:303-9. doi: 10.1016/j.ejmech.2015.08.006. Epub 2015 Aug 6.

Abstract

A series of hydroxyanthraquinones having an alkylating N-mustard pharmacophore at 1'-position were synthesized via a bioisostere approach to evaluate their cytotoxicity against four tumor cell lines (MDA-MB-231, HeLa, MCF-7 and A549). These compounds displayed significant in vitro cytotoxicity against MDA-MB-231 and MCF-7 cells, reflecting the excellent selectivity for the human breast cancer. Among them, compound 5k was the most cytotoxic with IC50 value of 0.263 nM and is more potent than DXR (IC50 = 0.294 nM) in inhibiting the growth of MCF-7 cells. The excellent cytotoxicity and good selectivity of compound 5k suggest that it could be a promising lead for further design and development of anticancer agents, especially for breast cancer.

Keywords: Anthraquinone; Antitumor activity; Nitrogen mustard; Synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthraquinones / chemical synthesis
  • Anthraquinones / chemistry
  • Anthraquinones / pharmacology*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Molecular Structure
  • Nitrogen Mustard Compounds / chemical synthesis*
  • Nitrogen Mustard Compounds / chemistry
  • Nitrogen Mustard Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-((bis(2-chloroethyl)amino)(4-fluorophenyl)methyl)-1,4-dihydroxyanthracene-9,10-dione
  • Anthraquinones
  • Antineoplastic Agents
  • Nitrogen Mustard Compounds