Preparation of Freestanding Conjugated Microporous Polymer Nanomembranes for Gas Separation

Conjugated microporous polymers (CMPs) have attracted much interest due to their intrinsic porosity, outstanding stability, and high variability. However, the processing of these materials for membrane application has been limited due to their insoluble nature when synthesized as bulk material. Here we report the synthesis of freestanding CMP-nanomembranes via layer-by-layer growth of a “click” based conjugated microporous polymer on a sacrificial substrate. After dissolution of the substrate the CMP-nanomembrane can be transferred to porous substrates and continuously cover holes of up to 50 μm diameter. The CMP-nanomembranes appear defect-free as inferred from high selectivity values obtained from gas permeation experiments and from electrochemical investigation in the presence of ferrocene. The presented synthesis method represents a versatile strategy to incorporate CMP materials in functional devices for membrane separation, catalysis, or organic electronics

Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach

A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor <b>16</b> displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC₅₀ values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker

Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach

A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor <b>16</b> displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC₅₀ values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker

Probing Factor Xa Protein–Ligand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands

The accurate prediction of protein–ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen−π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots