Structure-Based Drug Design and Identification of H 2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo

J Med Chem. 2018 Oct 11;61(19):8613-8624. doi: 10.1021/acs.jmedchem.8b00498. Epub 2018 Sep 27.


Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of H2O-soluble and orally bioavailable hexacyclic CPT derivatives. By analysis of a virtual chemical library and cytotoxicity screening in vitro, 9 and 11 were identified as potential prodrugs and chosen for further characterization in vivo. Both compounds exhibited remarkable anticancer and anti-inflammation efficacies in animals and improved drug-like profiles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Camptothecin / chemistry*
  • Camptothecin / pharmacology*
  • Cell Proliferation
  • Drug Design*
  • Humans
  • Lipopolysaccharides / toxicity
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Sepsis / chemically induced
  • Sepsis / drug therapy*
  • Sepsis / pathology
  • Solubility
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Lipopolysaccharides
  • Camptothecin