Preliminary study of mechanism of action of SN38 derivatives. Physicochemical data, evidence of interaction and alkylation of DNA octamer d(GCGATCGC)2

Magn Reson Chem. 2017 Feb;55(2):128-136. doi: 10.1002/mrc.4508. Epub 2016 Sep 18.

Abstract

The synthesis of water-soluble SN38 derivatives is presented, and their stability in solutions used during drug development studies has been investigated. A preliminary study of mechanism of action of 9-aminomethyl SN38 is presented. Using NMR techniques, the interaction of the oligomer d(GCGATCGC)2 is studied, showing that the terminal GC base pairs are the main site of interaction. Using pulsed field gradient spin echo and mass spectroscopy, evidence of a spontaneous alkylation reaction of the DNA oligomer with SN38 derivatives is presented. A proposed mechanism of reaction is suggested. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: DNA; MALDI MS; NMR; SN38 derivative; covalent binding.

MeSH terms

  • Alkylation
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Base Sequence
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemical synthesis
  • Camptothecin / chemistry
  • DNA / chemistry*
  • Drug Stability
  • Irinotecan
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Molecular Structure
  • Polydeoxyribonucleotides / chemistry
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Polydeoxyribonucleotides
  • Irinotecan
  • DNA
  • Camptothecin