Pravat Mondal

Pores containing molecular adapters provide internal selective binding sites, thereby allowing the stochastic sensing of analytes. Herein, we demonstrate that semiaza‐bambusuril (BU) acts as a non‐covalent molecular adapter when lodged within the lumen of the wild‐type α‐hemolysin (WT‐αHL) protein pore. Because the bambusurils are recognized as anion receptors, the anion binding site within the adapter‐nanopore complex allows the detection of chloride anions, thus converting a non‐selective pore into an anion sensor.

Pores containing molecular adapters provide internal selective binding sites, thereby allowing the stochastic sensing of analytes. Herein, we demonstrate that semiaza‐bambusuril (BU) acts as a non‐covalent molecular adapter when lodged within the lumen of the wild‐type α‐hemolysin (WT‐αHL) protein pore. Because the bambusurils are recognized as anion receptors, the anion binding site within the adapter‐nanopore complex allows the detection of chloride anions, thus converting a non‐selective pore into an anion sensor.

The rising interest in Kv7 modulators originates from their ability to evoke fundamental electrophysiological perturbations in a tissue-specific manner. A large number of therapeutic applications are, in part, based on the clinical experience with two broad-spectrum Kv7 agonists, flupirtine and retigabine. Since precise molecular structures of human Kv7 channel subtypes in closed and open states have only very recently started to emerge, computational studies have traditionally been used to analyze binding modes and direct the development of more potent and selective Kv7 modulators with improved safety profiles. Herein, the synthetic and medicinal chemistry of small molecule modulators and the representative biological properties are summarized. Furthermore, new therapeutic applications supported by in vitro and in vivo assay data are suggested.

This study confirms the hypothesis that bambusurils (BUs) with equatorial sulfur atoms cannot assume an anion-binding jigger conformation due to strong intramolecular van der Waals attractive interactions. NMR, X-ray crystallography, and computation with newly synthesized eq-semithio-BU[4] and ax-semiaza-eq-semithio-BU[4]s indicate that they all assume compact conformations. Intramolecular distances and a torsional angle serve as reliable indicators of the conformation of any BU. Chemoselective alkylation at the peripheral (equatorial) thiourea functions provides a convenient entry to novel hetero-BUs.

Bambusurils (BUs) are known to be rigid cavitands that feature an extended, jigger‐like conformation, and the BU[6]s strongly bind anions within their hydrophobic cavity. These features are not necessarily shared by the family of perthio‐BUs. This study reveals that perthio‐BUs assume a compact conformation and perthio‐BU[6]s are poor anion binders, crystallizing as anion‐free species from solutions containing halide salts. Computational studies show that the equatorial sulfur atoms compete against guest anions for binding with the glycoluril methine groups via strong van der Waals (vdW) attractive interactions. These competitive contacts not only account for the diminished anion‐binding of perthio‐BUs, but also explain their compact conformation. The semithio‐ and perthio‐BU[4]s form linear coordination polymers with Hg^II in the solid‐state regardless of their intrinsic molecular conformation. The strong involvement of sulfur atoms in intramolecular interactions differentiates the equatorial from the axial (peripheral) heteroatoms, thus offering chemoselective and regioselective transformations.