2. Academic Validation
  3. 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

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

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.

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