The design, synthesis, and evaluation of two universal doxorubicin-linkers: preparation of conjugates that retain topoisomerase II activity

Bioorg Med Chem Lett. 2006 Jan 1;16(1):104-7. doi: 10.1016/j.bmcl.2005.09.046. Epub 2005 Oct 18.

Abstract

The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3'-amino group of doxorubicin (DOX) permits the preparation of DOX conjugates via Michael addition of thiol-containing vectors. This method enables the mild, facile, and high-throughput preparation of DOX conjugates that retain the basic C3'-nitrogen, a pre-requisite for topoisomerase II inhibition. Seven DOX-amino acid conjugates were prepared, each displaying similar inhibitory activity as the parent drug.

MeSH terms

  • Aldehydes / chemistry*
  • Aldehydes / metabolism
  • Anthracyclines / pharmacology
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Chemistry, Pharmaceutical / methods*
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / metabolism*
  • Doxorubicin / chemistry*
  • Doxorubicin / pharmacology
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Humans
  • K562 Cells
  • Magnetic Resonance Spectroscopy
  • Maleimides / chemistry*
  • Models, Chemical
  • Nitrogen / chemistry

Substances

  • Aldehydes
  • Anthracyclines
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Maleimides
  • Doxorubicin
  • DNA Topoisomerases, Type II
  • Nitrogen