期刊
CHEMMEDCHEM
卷 17, 期 21, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200415
关键词
Cardiac glycosides; DNA damage response; Chk1 phosphorylation; Anticancer agents
资金
- NIH/NCI [R01CA230453]
Cardiac glycosides have been found to have anticancer activity in addition to their original use in treating heart diseases. This study successfully synthesized cardiac glycoside derivatives and identified structure-activity relationships that contribute to their anticancer activity. This finding is important for further optimization of cancer therapeutics.
Cardiac glycosides (CGs) are bioactive compounds originally used to treat heart diseases, but recent studies have demonstrated their anticancer activity. We previously demonstrated that Antiaris toxicaria 2 (AT2) possesses anticancer activity in KRAS mutated lung cancers via impinging on the DNA damage response (DDR) pathway. Toward developing this class of molecules for cancer therapy, herein we report a multistep synthetic route utilizing k-strophanthidin as the initial building block for determination of structure-activity relationships (SARs). A systematic structural design approach was applied that included modifications of the sugar moiety, the glycoside linker, stereochemistry, and lactone ring substitutions to generate a library of O-glycosides and MeON-neoglycosides derivatives. These molecules were screened for their anticancer activities and their impact on DDR signaling in KRAS mutant lung cancer cells. These results demonstrate the ability to chemically synthesize CG derivatives and define the SARs to optimize AT2 as a cancer therapeutic.
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