Ofer Reany

Artificial ion transporters offer promising avenues for therapeutic intervention by disrupting ionic homeostasis in cancer cells. Herein, we report the design, synthesis, and biological evaluation of a novel class of redox-switchable chloride channels based on selenide-containing semiaza -bambusurils. These macrocyclic compounds exhibit reversible transmembrane chloride transport activity modulated by the oxidation state of selenium side chains, enabling precise control over ion flux in response to cellular redox conditions. The reduced selenide form facilitates efficient H ⁺ /Cl ⁻ symport across lipid bilayers, thereby inducing apoptosis and inhibiting autophagy in cancer cells. Oxidation to selenoxide suppresses transport activity due to increased hydrophilicity, which is restored upon reduction by intracellular glutathione (GSH), demonstrating a dynamic ON/OFF switching mechanism. Single-channel conductance studies confirm unimolecular channel formation, and in vitro assays reveal potent cytotoxicity against multiple cancer cell lines. Cell-intrinsic mechanism studies have revealed an unusual, ultrafast form of cancer cell death induced by perturbation of intracellular chloride concentrations, leading to apoptotic cell death and the inhibition of autophagy. In vivo experiments using U87MG tumor-bearing mice show significant tumor growth inhibition with minimal systemic toxicity. This work represents the first example of a bambusuril-based artificial ion channel with reversible redox control and in vivo efficacy, offering a powerful platform for adaptive, targeted cancer therapies.

Substitution of the extended tribenzo-cyclononatriene transforms an achiral cavitand into a chiral host molecule. Calculations of the continuous chirality measure (CCM) predict that tangential substitution induces greater distortion of the unsubstituted bowl-shaped cavitand than radial substitution. We achieved the new cavitands through regioselective synthesis and named them Calochorturils (CTs) after the chiral C₃-symmetric Calochortus venustus tulip. Resolving them into optically pure enantiomers using chiral HPLC enabled their characterization by optical rotation and circular dichroism spectroscopy. Their absolute configuration was determined by X-ray crystallography of an enantiomerically pure triply etherified CT with (S)-BINOL. A comparison of CCM calculations for several solid-state CT derivatives with gas-phase models shows satisfactory agreement. The racemization rate constant for the bowl-to-bowl inversion, k_rac = 7.1 × 10^-6 s^-1, corresponds to an activation free energy barrier of ΔG^# = 115.1 kJ mol^-1. Notably, the CT skeleton is configurationally more stable than the CTV framework, with a 27 h half-life at 334 K in chloroform, compared with 8 h of CTV. Thus, CT derivatives can be handled in solution at room temperature without a significant loss of optical purity.

The development of new protocols for stereospecific and stereoselective halogenation transformations by mild reaction conditions is a highly desirable research target for the chemical and pharmaceutical industries. Following the straightforward methodology for directly transforming a wide scope of alcohols to alkyl bromides and chlorides using substoichiometric amounts of thioureas and N‐halo succinimides (NXS) as a halogen source in a single step, we noticed that in apolar solvents bromination of chiral secondary alcohols did not produce the expected racemates. In this study, the stereochemical aspects of the bromination reaction were examined. Surprisingly, bromination of (±)‐threo‐ or (±)‐erythro‐3‐phenyl‐2‐butanols revealed a single diastereomeric brominated product with retention of configuration. The scope of these reactions was expanded on several β‐aryl alcohols. During these studies, an unexpected stereospecific 1,2‐migration of the phenyl group was shown to take place. The proposed mechanism of the 1,2‐phenyl migration involves the formation of a spiro[2,5]octadienyl radical, which is then attacked by a bromide radical at any of the two cyclopropyl positions anti to the phenyl position, leading to products that retain the stereoisomeric configuration of the starting material.

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.

In the last two decades, perchlorate salts have been identified as environmental pollutants and recognized as potential substances affecting human health. We describe self‐assembled monolayers (SAMs) of novel semiaza‐bambus[6]urils (semiaza‐BUs) equipped with thioethers or disulfide (dithiolane) functionalities as surface‐anchoring groups on gold electrodes. Cyclic voltammetry (CV) with Fe(CN)₆^3−/4− as a redox probe, together with X‐ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM) and ellipsometry, were employed to characterize the interactions at the interface between the anchoring groups and the metal substrate. Data showed that the anion receptors′ packing on the gold strongly depends on the anchoring group. As a result, SAMs of BUs with lipoic amide side chains show a concentration‐dependent layer thickness. The BU SAMs are extremely stable on repeated electrochemical potential scans and can selectively recognize perchlorate anions. Our electrochemical impedance spectroscopy (EIS) studies indicated that semiaza‐BU equipped with the lipoic amide side chains binds perchlorate (2–100 mM) preferentially over other anions such as F⁻, Cl⁻, I⁻, AcO⁻, H₂PO₄⁻, HPO₄²⁻, SO₄²⁻, NO₂⁻, NO₃⁻, or CO₃²⁻. The resistance performance is 10 to 100 times more efficient than SAMs containing all other tested anions.