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.
Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.
Cardiac Glycosides (CGs) are used to treat congestive heart disease. Their application has since been extended to cancer treatment. While the mechanism of action is still unknown, it was previously believed that Na+/K+ ATPase might play a crucial role in cancer mitigation. However, we recently reported that cardiac glycosides could specifically enhance the anti-cancer effect of chemotherapy in KRAS mutant lung cancer by inhibiting the DNA Damage Response (DDR), and these effects were independent of the Na+/K+ ATPase. Mechanistically, we showed that cardiac glycosides induced the degradation of UHRF1, an important player in promoting DNA double strand break (DSB) repair through homologous recombination. These results suggest the promise of derivatizing cardiac glycosides into potential chemo sensitizing agents. Yet, one of the major challenges with these compounds is their cardiotoxicity. This has created a need for developing a strategy to generate less cardiotoxic drugs that are effective in inhibiting the DNA damage response to safe and effective anticancer activity. Herein we report a multi-step synthetic route utilizing k-strophanthidin as the initial building block. A systematic structural design was applied that included modification of the sugar moiety, glycoside linker, stereochemistry, and lactone ring to create a library of O-glycosides and MeON-neoglycosides. These molecules were screened for anti-cancer properties by exploring their influence on the signaling/expression of various downstream kinases in the DDR pathway. We discovered the inhibitory activity of O-glycosides to be more potent than the MeON-neoglycosides or benzylidene-lactone modified compounds. These results demonstrate the ability to chemically synthesize CG derivatives to optimize for anticancer activity with the goal of identifying less cardiotoxic CGs. Citation Format: Diana Ainembabazi, Xinran Geng, Navnath Gavande, YouWei Zhang, John Turchi. Design and synthesis of novel cardiac glycosides by targeting the DNA damage response for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1406.
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