Template‐Directed Synthesis of Bivalent, Broad‐Spectrum Hosts for Neuromuscular Blocking Agents**

Abstract

We report on the synthesis of bivalent water‐soluble calix[4]arene and calix[5]arene hosts, Super‐sCx4 and Super‐sCx5 as new broad‐spectrum supramolecular binders of neuromuscular blocking agents (NMBAs). Synthesis was achieved using the target bisquaternary amine NMBAs as a template to link two highly anionic p‐sulfonatocalixarene building blocks in aqueous solution. Bivalent anionic hosts Super‐sCx4 and Super‐sCx5 bind by engaging both quaternary amines present on a variety of NMBAs. We report low μM binding to structurally diverse alkyl, steroidal, curarine and benzylisoquinoline NMBAs with high selectivity over the neurotransmitter acetylcholine and a variety of other hydrophobic amines.

Highly Water-Soluble Cucurbit[8]uril Derivative as a Broad-Spectrum Neuromuscular Block Reversal Agent

“…The value of K a for the complex of M1•CisA was determined to be (1.08 ± 0.36) × 10 7 M −1 , which was highter compared to that of other known supramolecular reversal agents (Figure 1C,D; Entry 1 in Table 1). 10,12,13 The K a value for the complexes of M1•Roc, M1•Vec, and M1•Pan was determined to be (1.97 ± 0.47) × 10 7 M −1 , (2.15 ± 0.43) × 10 7 M −1 , and (1.72 ± 0.42) × 10 7 M −1 , respectively (Table 1 and Figure S26−S28), which was comparable with that of CB [8]. 21 With the same method, the K a value for the complexes of M2•CisA, M2•Roc, M2•Vec, and M2•Pan was determined to be (6.50 ± 0.90) × 10 5 M −1 , (1.1 ± 0.2) × 10 6 M −1 , (9.2 ± 0.5) × 10 5 M −1 , and (1.0 ± 0.1) × 10 6 M −1 , respectively, which was approximately 20-fold lower compared to that of host M1 (Table 1 and Figures S29−S32).…”

Applications of Synthetic Receptors in Bioanalysis and Drug Transport

“…It was therefore employed as the template to link two highly anionic p-sulfonatocalixarene building blocks, which otherwise are strongly repulsed from each other (Figure 2a). 31 After extraction of the decamethonium, the resultant bivalent calixarene receptors form 1:1 complexes with various NMBAs with micromolar dissociation constants (K d ), exhibit excellent selectivity over acetylcholine and hydrophobic monovalent ammonium ions, and provide a novel alternative to Sugammadex as NMBA reversal agents.…”

“…NMBAs have diverse biscationic structures, but are a common geometrically defined pharmacophore consisting of two alkyl ammonium ions separated by ∼14 Å. Decamethonium, the paradigmatic NMBA, can bind to two calixarene units, one at each NMe 3 + terminus. It was therefore employed as the template to link two highly anionic p -sulfonatocalixarene building blocks, which otherwise are strongly repulsed from each other (Figure a) . After extraction of the decamethonium, the resultant bivalent calixarene receptors form 1:1 complexes with various NMBAs with micromolar dissociation constants ( K d ), exhibit excellent selectivity over acetylcholine and hydrophobic monovalent ammonium ions, and provide a novel alternative to Sugammadex as NMBA reversal agents.…”

“…Right: NMBA-templated bivalent calixarene hosts with a flexible hydrazine linker. Reprinted with permission from ref , copyright 2021, Wiley. (b) Formation of “imprint-and-report” DCLs followed by in situ fluorescent indicator displacement analysis of targets, with the receptors colored in magenta, dyes in green, and analytes in cyan.…”

Further Dimensions for Sensing in Biofluids: Distinguishing Bioorganic Analytes by the Salt-Induced Adaptation of a Cucurbit[7]uril-Based Chemosensor

“…Synthetic receptors and chemosensing ensembles capable of distinguishing structurally similar bioorganic analytes are crucial for developing facile, low-cost, and parallelizable sensing methods that are applicable in molecular diagnostics. − In particular, macrocyclic systems, for example, cryptands, , calix­[ n ]­arenes, − cavitands, − naphthotubes, − and cucurbit­[ n ]­urils , can strongly bind biorelevant analyte classes, such as metabolites, neurotransmitters, steroids, or metal cations in aqueous media. Unfortunately, macrocyclic hosts are in most cases composed of a fully covalently linked organic framework, − and thus, it can be challenging and time-consuming to tune their binding properties through the synthesis of new macrocyclic derivatives.…”