1. Cucurbituril host–guest complexes and pseudorotaxanes with N-methylpiperidinium, N-methylpyrrolidinium, and N-methylmorpholinium cations in aqueous solution
Mona A. Gamal-Eldin, Donal H. Macartney*, Org. Biomol. Chem, 2013, 11, 1234–1241
The sodium salt of octakis(6-deoxy-6-S-mercaptopropionyl)-γ-cyclodextrin (Sugammadex) has been approved in Europe for the reversal of the eﬀects of these SNMBs, but concerns over patient allergic sensitivity (including possible anaphylaxic reactions to the host and host–drug complex) have prevented its approval in North America. Investigations are also underway to determine if Sugammadex is useful in reversing anaphylaxis induced by SNMBs and other highly allergenic drugs. Sugammadex binds the rocuronium, vecuronium, and pancuronium cations over the steroidal framework, with stability constants of 2.5 × 107, 1.0 × 107, and 2.6 × 106 dm3 mol-1, respectively. Very recently, Isaacs and coworkers have reported that anionic acyclic glycoluril tetramers bind rocuronium, encapsulating the steroid frame, with comparable or superior stability constants compared to Sugammadex. The monocations investigated in the present study are excellent models for binding of CB to the diﬀerent terminal cationic N-heterocyclic groups on the SNMBs, while the dicationic threading ligands model the distance between the two cationic sites in the SNMBs and acetylcholinesterase inhibitors. The stability constants for the binding of CB to N-alkyl,N-methylheterocycle cations would suggest that the use of CB as a reversal agent may have an opposite trend in binding strength: pancuronium > vecuronium > rocuronium, with complexations of the terminal cationic (alkylated or pro- tonated) N-heterocyclic groups. Investigations of the CB complexation of these SNMBs, and other drugs used to reverse their action, are in progress.
2. Novel amino-cyclodextrin cross-linked oligomer as eﬃcient carrier for anionic drugs: a spectroscopic and nanocalorimetric investigation
Valentina Giglio, Carmelo Sgarlata, Graziella Vecchio*, RSC Adv.,2015, 5, 16664–16671
Cyclodextrins (CyDs) are cyclic oligosaccharides α(1→4) of glucose which have been extremely appealing in diﬀerent fields over a long time. Investigations on native cyclodextrins and their exhaustively modied products have been widely reported. CyDs have been frequently used as building blocks as they can be linked both non covalently and covalently to diﬀerent molecules. The covalent conjugation to molecules with diﬀerent properties provides a very attractive approach in the building of multifunctional systems devoted to applications in supramolecular, bioinorganic, organic, pharmaceutical, material chemistry and separation sciences. A number of CyD conjugates with amines, amino acids, peptides and aromatic systems have been reported over the years. The functionalization with suitable moieties has been shown to improve the metal binding ability leading to a wide range of applications. Many examples of CyD derivatives whose OH groups have been alkylated, esterified or easily randomly derivatized have been reported in the literature and mostly used for the formation of inclusion complexes. The total or partial modification of the OH groups aﬀects the solubility of CyDs in water or in organic solvent and, in some cases, allows for the introduction of charged groups. A successful example is sugammadex, a cyclodextrin derivative with carboxylic groups designed to selectively reverse the eﬀect of rocuronium. Some cyclodextrins, such as hydroxypropyl b-cyclodextrins (HP-CyD), have been approved by FDA as therapeutic agents to remove cholesterol from blood.
3. In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs
Shweta Ganapati, Peter Y. Zavalij, Matthias Eikermann*, Lyle Isaacs*, Org. Biomol.Chem,2016, 14,1277–1287
Annually, more than 400 million patients receive curare-type neuromuscular blocking agents (NMBAs) during surgical procedures in operating rooms, intensive care units, and emergency medicine departments. NMBAs such as rocuronium and cisatracurium are often used as an essential adjunct to general anesthesia to block neuromuscular transmission (muscle relaxation) dose-dependently which facilitates endotracheal intubation, optimizes surgical conditions, and prevents potentially harmful movements during surgery. To speed up the recovery of the muscle function of the patient and to prevent residual neuromuscular block, it is often necessary to reverse the biological eﬀect of NMBAs at the end of the surgery. A major advance in the clinical practice of anesthesia was made by the introduction of a γ-cyclodextrin-derived molecular container known as Sugammadex, which binds rocuronium with high aﬃnity in water and reverses the eﬀects of rocuronium in vivo. Sugammadex reverses neuromuscular block by sequestering rocuronium in the bloodstream, thereby depleting its concentration at the neuromuscular junction.