Discovery of lysosome-targeted covalent anticancer agents based on isosteviol skeleton
Discovery of lysosome-targeted covalent anticancer agents based on isosteviol skeleton
复制标题
基于异甜菊醇骨架的溶酶体靶向共价抗癌药物的发现
DOI：
10.1016/j.ejmech.2020.112896
复制
发表时间：
2021-01-01
影响因子：
6.7
通讯作者：
Lou, Hongxiang
中科院分区：
文献类型：
--
作者：
Liu, Jun;Li, Lin;Lou, Hongxiang
Covalent drugs play corresponding bioactivities by forming covalent bonds with the target, which possess many significant pharmacological advantages including high potency, ligand efficiency, and long-lasting effects. However, development of covalent inhibitors is a challenge due to their presumed indiscriminate reactivity. Here, we report the discovery of series of lysosome-targeting covalent anticancer agents by introducing nitrogenous bases to the modified isosteviol skeleton in order to minimize the toxicity and increase the selectivity. By introducing the electrophilic alpha, beta-unsaturated ketones into the A- and D-rings of isosteviol, the cytotoxicity of the obtained compounds were greatly increased. Further nitrogen- containing modifications to the D-ring led to the discovery of novel molecules that targeted lysosomes, and of which, compound 30 was the most potent and selective antiproliferative one to kill A549 cells in vitro and in vivo. Mechanism investigation revealed that compound 30 was trapped into lysosomes and damaged lysosomes to cause cell death. (c) 2020 Elsevier Masson SAS. All rights reserved.
