Cyclopent[a]anthraquinones as DNA intercalating agents with covalent bond formation potential: synthesis and biological activity

J Med Chem. 1996 Jul 5;39(14):2812-8. doi: 10.1021/jm950881y.

Abstract

A series of mitomycin C (MMC) analogues, namely cyclopentanthraquinone derivatives, were synthesized via Diels-Alder cyclization of naphthoquinone with 1-vinylcyclopent-1-enes. These new compounds are planar structures, like MMC, and bear an aziridine ring and a methyl carbamate side chain. After bioreduction, they are anticipated to be capable of intercalating into double-stranded DNA and bind covalently. Structure-activity relationships were studied. Of these compounds, 2,3-aziridino-4-[[(methylamino)carbonyl]methyl] cyclopent[alpha]anthracene-6,11-dione (4) was shown to have inhibitory activity against several leukemic and solid tumor cell lines. Mice (BDF1) bearing Lewis lung adenocarcinoma were treated with 4 and MMC (i.p., QD x 5). At a dose of 30.0 mg/kg, compound 4 was as effective as MMC (0.8 mg/kg). Compound 4 appears to be less toxic than MMC. DNA unwinding assay indicated that 4 is able to intercalate into DNA double strands and is also a topoisomerase II inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anthraquinones / chemical synthesis*
  • Anthraquinones / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cricetinae
  • DNA / drug effects*
  • Drug Screening Assays, Antitumor
  • HL-60 Cells
  • Humans
  • Intercalating Agents / chemical synthesis*
  • Intercalating Agents / pharmacology
  • Mitomycin / pharmacology
  • Mitomycins*
  • Molecular Structure
  • Tumor Cells, Cultured

Substances

  • Anthraquinones
  • Antineoplastic Agents
  • Intercalating Agents
  • Mitomycins
  • Mitomycin
  • DNA