SYNTHESIS AND MOLECULAR RECOGNITION PROPERTIES OF ACYCLIC CUCURBIT[N]URIL AND ITS DERIVATIVES

Abstract

The study of molecular containers has accelerated dramatically since the 1960's. The introduction of cucurbit[n]urils has contributed tremendously and continues to contribute to the expansion of the field. Chapter 1 introduces cucurbit[n]urils and their molecular recognition properties toward amino acids, peptides, and Insulin. Followed by an overview of the history of CB[n] and their analogs made with modified glycoluril backbone, solubilizing groups, alkyl arm linker, and type of aromatic arms. Chapter 2 describes the application of the acyclic CB[n], Calabadion 1 and 2 for the molecular recognition of amino acids, peptides, and Insulin. The results show that 1 and 2 have preferential binding affinity toward aromatic (e.g. H-Phe-NH2) and di-cationic (e.g. H-Lys-NH2) amino acid amides. Electrostatic interactions between the tetraanionic 1 and 2 with the amino acid guests (in their N-acetylated, zwitterionic, or CO-NH2 forms) was demonstrated to dramatically influence the strength of the recognition process. The binding affinity of 1 and 2 toward insulin was compared to that of CB[7], respectively (Ka= 1.32 × 10^5 M^-1 for 1, 3.47 × 10^5 M^-1 for 2, and 5.59 × 10^5 M^-1 for CB[7]) which showed comparable levels of affinity between these three hosts. Chapter 3 introduces a new acyclic CB[n] featuring a central glycoluril trimer with sulfonated triptycene aromatic sidewalls. It was observed that the binding affinity increases as the alkyl chain length of the guest increases. An x-ray crystal structure reveals an overall out-of-plane distortion of the aromatic sidewalls and intermolecular packing driven by interactions between the external faces of the triptycene sidewalls. Finally, the trimer host was shown to bind strongly to fentanyl which suggests potential usage as in vivo reversal agent.

In chapter 4, an analog of 1 was synthesized in which the (CH2)3 linking group was removed. This structural change brings the anionic sulfate substituents closer to the electrostatically negative ureidyl C=O portals. We find that this new host displays preferential binding affinity toward quaternary ammonium ioins and a higher binding affinity toward dications compared to 1. Most impressive are the nanomolar binding affinities toward rocuronium and vecuronium which suggests potential application for in vivo reversal agent.