ACYCLIC CUCURBIT[N]URIL CONGENERS: SYNTHESIS, BINDING PROPERTIES AND MEDICINAL APPLICATIONS

Abstract

An urgent problem for pharmaceutical industry is that the water solubility of an estimated 40-70% of the newly developed active pharmaceutical ingredients (API) are so poor that they cannot be formulated on their own. One interesting topic is to use molecular containers as the solubilizing agents. Supramolecular chemistry has always been an interesting research area and during the past decades, various new supramolecular host*guest systems have been developed. Cucurbit[n]urils (CB[n]) are very promising molecular containers as drug delivery vehicles due to their outstanding recognition properties. In order to discover the most suitable CB[n]-type containers as solubilizing agents, acyclic CB[n]-type containers have been synthesized and their recognition and formulation properties have been studied. In this thesis, three chapters have been included to investigate the possibility of using CB[n]-type containers as solubilizing agents for pharmaceutical agents.

Chapter 1 gives an introduction to supramolecular chemistry and formulation techniques using molecular containers. A literature review on the synthesis, functionalization and applications of cucurbit[n]uril is given and the application of cyclodextrins and CB[n] containers in formulation techniques is discussed.

Chapter 2 describes a series of acyclic CB[n]-type molecular containers (II-2a - II-2h) with different solubilizing groups bearing different charges for evaluation as potential drug solubilizing agents. The X-ray crystal structures of the negative, positive and neutral hosts (host II-2b, II-2f, and II-2h) are reported. For neutral (II-2h) and positively charged (II-2f) hosts, intramolecular H-bonds and ion-dipole interactions between the solubilizing arms and the ureidyl C=O portals are observed as well as intrahost π−π stacking interactions which results in a self-filling of the cavity. 1H NMR and UV/Vis spectroscopy are used to measure the Ka values of hosts II-2a, II-2h, and II-2f toward guests with different charge and significant decrease is noted in binding affinities of the neutral (II-2h) and positive (II-2f). The pKa of 7H+ alone and in the presence of differently charged hosts II-2a, II-2h, and II-2f are measured and the II-2a induces the largest pKa shift. The poor recognition properties of hosts II-2h and II-2f are reflected in their phase-solubility diagrams with insoluble drugs (tamoxifen, 17-α-ethynylestradiol, and indomethacin). In all cases, the anionic host II-2a functions more efficiently as a solubilizing agent than either neutral II-2h, or cationic host II-2f.

In chapter 3, we compare the ability of III-1a - III-1e to solubilize insoluble drugs relative to HP-β-CD. Phase solubility diagrams are created for mixtures of containers III-1a - III-1e and HP- β-CD with 19 drugs. We find that the solubilizing ability of the best container (III-1a - III-1e) is superior to HP-β-CD in all cases. A notable achievement is the solubilization of the developmental anticancer agent PBS-1086. The acyclic CB[n]-type containers display an affinity for the steroid ring system, aromatic moieties of insoluble drugs, and cationic ammonium groups. Compound III-1b is generally the most potent (Ka up to and exceeding 106 M-1) container whereas both III-1a and III-1b display excellent solubility enhancement toward a broad range of insoluble drugs. The broad scope of insoluble drugs that can be formulated with III-1a and III-1b - in many cases where HP- β-CD fails completely - makes acyclic CB[n]-type containers particularly attractive alternatives to cyclodextrins as solubilizing excipients for practical applications.