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

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.

Decarbonylative Olefination of Aldehydes to Alkenes.

New atom-economical alternatives to Wittig chemistry are needed to construct olefins from carbonyl compounds, but none have been developed to-date. Here we report an atom-economical olefination of carbonyls via aldol-decarbonylative coupling of aldehydes using robust and recyclable supported Pd catalysts, producing only CO and H2O as waste. The reaction affords homocoupling of aliphatic aldehydes, as well as heterocoupling of aliphatic and aromatic ones. Computations provide insight into the selectivity and thermodynamics of the reaction. The tandem aldol-decarbonylation reaction opens the door to exploration of new carbonyl reactivity to construct olefins.

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

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.

Correction: Transfer hydrogenation of carbon dioxide and bicarbonate from glycerol under aqueous conditions.

Correction for 'Transfer hydrogenation of carbon dioxide and bicarbonate from glycerol under aqueous conditions' by Jacob M. Heltzel et al., Chem. Commun., 2018, 54, 6184-6187.

Microwave-Assisted Decarbonylation of Biomass-Derived Aldehydes using Pd-Doped Hydrotalcites.

Catalytic decarbonylation is an underexplored strategy for deoxygenation of biomass-derived aldehydes owing to a lack of low-cost and robust heterogeneous catalysts that can operate in benign solvents. A family of Pd-functionalized hydrotalcites (Pd-HTs) were synthesized, characterized, and applied to the decarbonylation of furfural, 5-hydroxymethylfurfural (HMF), and aromatic and aliphatic aldehydes under microwave conditions. This catalytic system delivered enhanced decarbonylation yields and turnover frequencies, even at a low Pd loading (0.5 mol %). Furfural decarbonylation was optimized in a benign solvent (ethanol) compatible with biomass processing; HMF selectively afforded an excellent yield (93 %) of furfuryl alcohol without humin formation; however, a longer reaction favored the formation of furan through tandem alcohol dehydrogenation and decarbonylation. Yields of the substituted benzaldehydes (37-99 %) were proportional to the calculated Mulliken charge of the carbonyl carbon. Activity and selectivity reflected loading-dependent Pd speciation. Continuous-flow testing of the best Pd-HT catalyst delivered good stability over 16 h on stream, with near-quantitative conversion of HMF.

Transfer hydrogenation of carbon dioxide and bicarbonate from glycerol under aqueous conditions.

The transfer hydrogenation of CO2 from glycerol to afford formic and lactic acid is a highly attractive path to valorizing two waste streams and is a significantly more thermodynamically favorable process than direct CO2 hydrogenation. We report the first homogeneous catalyst for this transformation consisting of a water-soluble Ru N-heterocyclic carbene complex. The catalyst affords lactic and formic acid selectively in the presence of a base at temperatures between 150 and 225 °C. Carbonate salts can also be utilized in place of CO2, affording the same products at higher rates.