Structure-Based Drug Design and Identification of H2O-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.
Peichen Pan  1 ,  Jiean Chen  2 ,  Xijian Li  2 ,  Miyang Li  2 ,  Huidong Yu  3 ,  Jean J Zhao  4  5 ,  Jing Ni  4  5 ,  Xuwen Wang  1 ,  Huiyong Sun  1 ,  Sheng Tian  6 ,  Feng Zhu  1 ,  Feng Liu  6 ,  Yong Huang  2 ,  Tingjun Hou  1  7
Affiliations
  • 1. College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China.
  • 2. State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics , Peking University, Shenzhen Graduate School , Shenzhen , Guangdong 518055 , China.
  • 3. Rongene Pharma Co., Ltd. , Guangzhou , Guandong 510663 , China.
  • 4. Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
  • 5. Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02215 , United States.
  • 6. College of Pharmaceutical Sciences , Soochow University , Suzhou , Jiangsu 215123 , China.
  • 7. State Key Lab of CAD&CG , Zhejiang University , Hangzhou , Zhejiang 310058 , China.
PMID: 30227711 DOI: 10.1021/acs.jmedchem.8b00498
Abstract

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.