Enantioselective Transformations from Nitriles to NH2 -α-Tertiary Amines.

Organic molecules, containing one or more amine chiral centers, are very common to see in natural products and medicines. Although a large number of methods have been developed to afford enantiopure amines, most of the known approaches are limited with various reasons. For example, many methodologies start from nitrogen protected and activated substrates, which usually need multistep operations and seriously decrease the atom economy. Here we disclose a new catalytic strategy from commercial nitriles to high enantioselective α-tertiary primary amines in up to 90 % yield and 95 % enantiomeric excess. This transformation firstly undergoes an addition process of organolithium reagents to nitriles to generate the imine intermediates in situ. Subsequently, the most challenging step is by employing copper catalytic enantioselective addition of AllylBpin to the imine intermediates to form the final amines in one pot.

Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation.

Prostate cancer (PCa) represents the second cause of cancer death in adult men. Aberrant overexpression of UHRF1 has been reported in several cancer types, and is regarded as a novel drug target for cancer therapy. Nevertheless, no UHRF1-targeted small molecule inhibitor has been testing in clinical trials. Traditional Chinese medicine (TCM) prescriptions have a long history for the treatment of PCa in China, and Chinese herbal extracts are important resources for new drug discovery. In the present study, we first screened the potentially effective components from the commonly used TCMs for PCa treatment in clinic by using network pharmacology together with molecular docking. We identified diosgenin (DSG) as a small molecule natural compound specifically targeting UHRF1 protein. Furthermore, we validated the results by using the wet lab experiments. DSG, by directly binding UHRF1 protein, induced UHRF1 protein degradation through the ubiquitin-proteasome pathway. Importantly, DSG induced UHRF1 protein degradation by reducing the protein interaction with a deubiquitinase USP7. DSG reduced the level of genomic DNA methylation, and elevated the expression of such tumor suppressor genes as p21, p16 and LXN, thereby resulting in cell cycle arrest, cellular senescence and the inhibition of xenograft tumor growth. We here presented the first report that DSG specifically induced UHRF1 protein degradation, thereby revealing a novel anticancer mechanism of DSG. Altogether, this present study provided a promising strategy to discover new molecule-targeted drugs from small-molecule natural products.