期刊
MOLECULAR PHARMACEUTICS
卷 15, 期 8, 页码 3020-3031出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b00003
关键词
ruthenium arene Schiff-base complexes; anticancer; p53-independent activity; reactive oxygen species; endoplasmic reticulum stress
资金
- Ministry of Education
- National University of Singapore [R143-000-638-112]
- Ligue contre le cancer, CNRS, European COST action [CM1105]
Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its pi-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds.
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