Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response

Abstract

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.

The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

“…UHRF1 is a multifunctional protein with roles in epigenetic maintenance and as a DNA damage sensor. Building upon that, we recently reported a series of chemical modifications of AT2 and their effects on impacting chemotherapy sensitivity in a lung cancer model [ 38 ], revealing innovative insights into the structure of CGs in inhibiting the DDR and DSB repair.…”

“…These questions can only be answered following a systematic SAR to identify the suitable features of CGs that enhance their activity. Our groups and several others have published different SAR results [ 20 , 38 , 52 , 90 ]. However, a comprehensive investigation would be necessary to not only identify relevant structure moieties, but also discern which signaling pathways are activated and consequently trigger other pathways.…”

“…Hence, targeting and inhibiting the DDR pathway is a viable strategy in cancer therapy due to the reliance of cancer cells on DDR to mitigate the effects of replication stress. The anti-cancer activity of CGs has been demonstrated in some studies to target the DDR by regulating the expression and activity of certain proteins and kinases in the pathway to drive cancer cells into cell cycle arrest, apoptosis, or autophagy-dependent cell death [ 32 , 38 ].…”

An in silico approach to investigate the theranostic potential of coumarin‐derived self‐immolative luminescent probes

“…[3][4][5] Therefore, the quest for unique and efficient methods that can overcome the existing limitations has always been on the top of priorities. With the advent of nanotechnology, [6] advancements in chemical synthesis [7][8][9] and identification of luminescent probes, [10][11][12][13] the integration of diagnosis and treatment has become easier. Recently, the advancements made towards the development of novel therapeutics with other platinum metal complexes were reviewed, highlighting the need to search alternates for the existing and well established drug cisplatin.…”