Synthesis and preliminary bioevaluation of novel E-ring modified acetal analog of camptothecin as cytotoxic agents

Eur J Med Chem. 2012 Oct:56:1-9. doi: 10.1016/j.ejmech.2012.07.050. Epub 2012 Aug 7.

Abstract

In an effort to improve the metabolic stability of the E-ring and decrease the toxicity of camptothecin (CPT), a novel cytotoxic acetal analog with 21-alkoxy groups was designed and synthesized. The preliminary results revealed that this class of compounds showed superior antiproliferative activity in vitro and moderate in vivo activity, while their topoisomerase I (Topo I) inhibitory activity was weakened significantly. The implications of these results within the current understanding of the structure-activity relationship of camptothecin are analyzed in detail. The obtained information provides insight into the role of the 21-carbonyl group in the binding of CPT to Topo I-DNA complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemical synthesis
  • Camptothecin / chemistry
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type I / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • DNA Topoisomerases, Type I
  • Camptothecin