Structure-Based Drug Design and Identification of H2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo

Journal of Medicinal Chemistry
Peichen PanTingjun Hou

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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Citations

Jun 19, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Michele MontaruliOrazio Nicolotti
Aug 16, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Christian Bailly
Jul 11, 2020·European Journal of Medicinal Chemistry·Shu FanSan-Qi Zhang
May 31, 2021·European Journal of Medicinal Chemistry·Antonino LauriaAnnamaria Martorana
Jan 7, 2022·Dalton Transactions : an International Journal of Inorganic Chemistry·Yun-Qiong GuHong Liang

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