Oligosaccharide-camptothecin conjugates as potential antineoplastic drugs: Design, synthesis and biological evaluation

Eur J Med Chem. 2020 Sep 15:202:112509. doi: 10.1016/j.ejmech.2020.112509. Epub 2020 Jun 30.

Abstract

Thirty novel 20 (S)-O-linked camptothecin (CPT) glycoconjugates were synthesized. They showed more potent in vitro cytotoxicities over irinotecan, but very weak direct topoisomerase I (Topo I) inhibition was observed at 100.0 μM. Oligosaccharide types, length of a PEG linker and acetyl groups exerted obvious effects on cytotoxicity, selectivity, water solubility and stability of the newly synthesized CPT glycoconjugates. Construct 40, with a bleomycin (BLM) disaccharide linked to diethylene glycol in the introduced ester moiety, demonstrated a superior antitumor activity and a distinct selectivity compared to CPT. No toxicity was detectable in animal acute toxicity intravenously (160 mg/kg). Collectively, attachment of oligosaccharides with tumor targeting to 20 (S)-OH of CPT could offer a solution to the daunting problems posed by current Topo I poisons.

Keywords: Anti-tumor activity; Aqueous solubility and stability; Camptothecin; Oligosaccharides; Toxicological assessment.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Camptothecin / chemistry
  • Camptothecin / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • DNA Topoisomerases, Type I / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Molecular Structure
  • Oligosaccharides / chemistry
  • Oligosaccharides / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology*

Substances

  • Antineoplastic Agents
  • Oligosaccharides
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • Camptothecin