Design and synthesis of a DNA-crosslinking azinomycin analogue

Org Biomol Chem. 2005 Oct 7;3(19):3585-9. doi: 10.1039/b508908e. Epub 2005 Sep 5.

Abstract

The azinomycins are potent antitumour antibiotics that are able to crosslink DNA, but are relatively unstable and unlikely to progress as therapeutic candidates. A prototype analogue 4 with more clinical potential has been designed and synthesised and incorporates the epoxide function of the azinomycins and a nitrogen mustard. Two further analogues 5 and 6 that can alkylate DNA but cannot crosslink the duplex have also been synthesised. Compound 4 crosslinks DNA efficiently at nM concentrations. Compounds 4-6 were submitted to the NCI 60 cell line screen and have similar antitumour activity, although 4 is slightly less active than the non-crosslinking compounds. These observations will be important in the design of further azinomycin analogues with antitumour activity.

MeSH terms

  • Alkylation
  • Antibiotics, Antineoplastic / chemical synthesis*
  • Azabicyclo Compounds
  • Cross-Linking Reagents / chemical synthesis*
  • DNA / chemistry*
  • Dipeptides
  • Drug Screening Assays, Antitumor
  • Epoxy Compounds / chemistry
  • Glycopeptides / chemical synthesis*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mechlorethamine / pharmacology
  • Models, Chemical
  • Naphthalenes / chemical synthesis
  • Peptides / chemical synthesis*
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • Azabicyclo Compounds
  • Cross-Linking Reagents
  • Dipeptides
  • Epoxy Compounds
  • Glycopeptides
  • Intercellular Signaling Peptides and Proteins
  • Naphthalenes
  • Peptides
  • azinomycin B
  • azinomycin A
  • Mechlorethamine
  • DNA