Translating aqueous CO2 hydrogenation activity to electrocatalytic reduction with a homogeneous cobalt catalyst.

A molecular cobalt CO2 hydrogenation catalyst was explored for electrocatalytic CO2 reduction under aqueous conditions. The resulting pH-dependent selectivity between H2 and HCO2- is rationalized with thermodynamic analysis and stoichiometric experiments.

Reducing CO2 to HCO2- at Mild Potentials: Lessons from Formate Dehydrogenase.

The catalytic reduction of CO2 to HCO2- requires a formal transfer of a hydride (two electrons, one proton). Synthetic approaches for inorganic molecular catalysts have exclusively relied on classic metal hydrides, where the proton and electrons originate from the metal (via heterolytic cleavage of an M-H bond). An analysis of the scaling relationships that exist in classic metal hydrides reveal that hydride donors sufficiently hydridic to perform CO2 reduction are only accessible at very reducing electrochemical potentials, which is consistent with known synthetic electrocatalysts. By comparison, the formate dehydrogenase enzymes operate at relatively mild potentials. In contrast to reported synthetic catalysts, none of the major mechanistic proposals for hydride transfer in formate dehydrogenase proceed through a classic metal hydride. Instead, they invoke formal hydride transfer from an orthogonal or bidirectional mechanism, where the proton and electrons are not colocated. We discuss the thermodynamic advantages of this approach for favoring CO2 reduction at mild potentials, along with guidelines for replicating this strategy in synthetic systems.

Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity.

Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDH1A1) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.