Functionalized Acyclic Cucurbit[n]uril Molecular Containers as Reversal Agents for Drugs

Abstract

The study of molecular containers has a prominent place in the scientific literature with many applications, including drug reversal. The clinical use of the cyclodextrin based reversal agent BridionTM has greatly improved the post-operative safety of patients who undergo surgery aided by NMBAs such as rocuronium. Chapter 1 introduces molecular containers, CB[n], and reports the use of the acyclic CB[n] known as Calabadion 2 as a broad spectrum reversal agent for NMBAs in rats. It also proposes the potential use of molecular containers as reversal agents for the treatment of overdose of illicit drugs in the context of available therapies. Chapter 2 establishes that Calabadion 2 displays good to high levels of selectivity toward the NMBAs rocuronium, vecuronium, and cisatracurium both in vitro and based on simulations designed to capture the essence of the biological system. The excretion profile of Calabadion 2 after NMBA reversal in rats was studied by a 1H NMR assay. It is reported that more than 50% of Calabadion 2 is eliminated intact by the kidneys within 1 hour. Chapter 3 establishes that CB[n] based molecular containers - Calabadion 1, Calabadion 2, and CB[7] display higher affinities than p-sulfocalix[4]arene and HP-β-cyclodextrin toward a panel of illicit drugs for which there are currently no USFDA approved pharmacotherapies. Calabadion 2 but not CB[7] is able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The excretion profile of fentanyl and Calabadion 1 post reversal in rats was studied by HPLC and 1HNMR. It is reported that on an average 24 % fentanyl and 40% Calabadion 1 are eliminated by the kidneys within 1 hour. Chapter 4 discusses the synthesis and molecular recognition properties of three new acyclic CB[n] hosts IV-2a – IV-2c which incorporate alkyl linkers of varying lengths- ethyl, hexyl, and decyl; capping one end of Calabadion 1. These hosts were less water soluble than Calabadion 1 due to the loss of two sulfonate groups and did not undergo intermolecular self-association. However, the intramolecular self-inclusion of the alkyl linkers inside the cavity of these hosts led to decreased binding affinities toward guests compared to Calabadion 1.