2. Academic Validation
  3. Discovery of lysosome-targeted covalent anticancer agents based on isosteviol skeleton

Discovery of lysosome-targeted covalent anticancer agents based on isosteviol skeleton

  • Eur J Med Chem. 2021 Jan 1:209:112896. doi: 10.1016/j.ejmech.2020.112896.
Jun Liu 1,  Lin Li 2,  Xiaobin Li 3,  Xin Wang 4,  Xiaoyu Zhao 2,  Yanan Qiao 2,  Yuliang Xu 2,  Yong Sun 2,  Lilin Qian 2,  Zhaopeng Liu 2,  Aiguo Ji 2,  Hongxiang Lou 5
Affiliations

Affiliations

  • 1 Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China; School of Pharmacy, Qingdao University, Qingdao, 266071, China.
  • 2 Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
  • 3 Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong, 250103, China.
  • 4 School of Pharmacy, Qingdao University, Qingdao, 266071, China.
  • 5 Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China. Electronic address: louhongxiang@sdu.edu.cn.
PMID: 33097300 DOI: 10.1016/j.ejmech.2020.112896
Abstract

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 α, β-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.

Keywords

Covalent inhibitors; Five-membered unsaturated lactone; Isosteviol; Lysosomes; α; β-Unsaturated ketone.

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