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.

The catalytic reduction of CO 2 to HCO 2 − 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 CO 2 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 CO 2 reduction at mild potentials, along with guidelines for replicating this strategy in synthetic systems.

The instruction of high enrollment general and organic chemistry laboratories at a large public 10 university always have curricular, administrative, and logistical challenges. Herein, we describe how we met these challenges in the transition to remote teaching during the COVID-19 pandemic. We discuss the reasoning behind our approach, the utilization of our existing web-based course content, the additions and alterations to our curriculum, replacement of experimental work with videos, the results of both student and TA surveys, and lessons learned for iterations of these courses in the near 15 future. File list (3) download file view on ChemRxiv CHEMRXIV_REVISED-Online in No Time.pdf (1.34 MiB) download file view on ChemRxiv Online in No Time Supporting Information.pdf (181.10 KiB) download file view on ChemRxiv bigbrother_python_code.py (3.15 KiB)

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 bi-directional mechanism, where the proton and electron are not co-located. 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.