Host-Guest Complexes of Cucurbit[7]uril With Cationic Drugs and Amino Acid Derivatives

Abstract

The host-guest chemistry between cucurbit[7]uril (CB[7]) and cationic organic guests of medicinal and biological interest are described in this thesis. In the first part, three cationic steroidal neuromuscular blockers (SNMBs) were studied, along with guests that model their monocationic N-alkyl-N-methylheterocyclic (morpholinium, pyrrolidinium and piperidinium) terminal groups of the SNMBs, and dicationic guests in which the two N-methylheterocyclic rings are linked by a decamethylene chain, modelling a variety of NMBs. Other cationic drugs related to acetylcholine processes in neuromuscular blockage were also studied. In the second part, the amino acids lysine, and its mono-, di- and trimethylated and acetylated Nε derivatives, and arginine, and mono- and (symmetric and asymmetric) dimethylarginine, were investigated as guests, along with analogs of arginine. The nature and strength of the complexation between CB[7] and these guests in aqueous solution were determined by 1H NMR spectroscopy and ESI mass spectrometry. The CB[7] showed high binding affinity (KCB[7] = 106-109 M-1) towards the N-alkyl-N-methylheterocyclic cations with a trend of piperidinium > pyrrolidinium > morpholinium, which reflects the relative hydrophobicities of the guests. The CB[7] forms 1:1 and 2:1 host-guest complexes with dicationic model guests, with the CB[7] initially encapsulating the decamethylene chain. The second CB[7] binds to a terminal site, resulting in electrostatic repulsions with the first CB[7], which are resolved by the translocation of the first CB[7] to the opposite terminal site. This 2:1 binding mode is also observed with CB[7] and the SNMBs, and the trend in KCB[7] with these SNMB terminal sites is comparable to that observed for the monocationic model guests. The other cationic drugs also form stable host-guest complexes with CB[7], and the binding constants displayed dependences on the size, charge, and hydrophobicity of the guests. The CB[7] exhibits significant selectivity towards different lysine and arginine derivatives, which can be related to the relative hydrophobicity afforded by the methyl substituents and the positioning of the guest within the CB[7] cavity. The 3500-fold selectivity for Nε,Nε,Nε-trimethyllysine over lysine by CB[7] is the highest observed for a synthetic macrocyclic receptor, while a modest selectivity of symmetrical over asymmetrical dimethylarginine by CB[7] is observed.