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

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.

Author information

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.

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.

PMID:
30227711
PMCID:
PMC6668024
[Available on 2019-10-11]
DOI:
10.1021/acs.jmedchem.8b00498

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