This thesis describes the host-guest chemistry between cucurbit[7]uril (CB[7]) and various series of guests, including neutral polar organic solvents, bis(pyridinium)alkane dications, local anaesthetics, acetylcholine analogues, as well as succinylcholine and decamethonium analogues, in aqueous solution. A focus of this thesis is the effects of varying the chemical structures within different series of guests upon the nature of the host-guest chemistry, such as the relative position and orientation of the guest relative to the CB[7] cavity, and the strengths of the binding affinities. The binding affinities of polar organic solvents with CB[7] depend upon the hydrophobic effect and dipole-quadrupole interactions. The polar guests align themselves so that their dipole moment is perpendicular to the quadrupole moment of CB[7]. The binding strengths of acetone and acetophenone to CB[7] decrease in the presence of alkali metals. Discrete 1:1 and 2:1 host-guest complexes are formed between CB[7] and a series of bis(pyridinium)alkane guests. In most cases the CB[7] initially occupies the aliphatic linker when the 1:1 complex is formed and migrates to the terminal regions as the second CB[7] is added. When bulky, hydrophobic tert-butyl substituents are present, however, the CB[7] occupies the terminal pyridinium region and not the central linker. Supramolecular complexes between CB[7] and a series of local anaesthetics have binding affinities 2-3 orders of magnitude greater than reported values with beta-cyclodextrin. The first pKa values of the guests increase by 0.5-1.9 units upon complexation. The binding positions of the guests within CB[7] differ in neutral and acidic media, with the systems thus behaving as pH-activated switches. With supramolecular complexes between CB[7] and various cationic cholines and their phosphonium analogues, the CB[7] cavity is occupied by the charge-diffuse cationic region. The binding affinities and positions vary depending on the nature of the onium group as well as the substituents within the guest molecule. Host-guest complexes between CB[7] and dicationic acetylcholinesterase inhibitors have very strong 1:1 binding affinities, with 2:1 binding being significantly weaker. These binding affinities are related to the nature of the cationic onium groups, and the length and hydrophobicity of the connecting linkers. / Thesis (Ph.D, Chemistry) -- Queen's University, 2010-01-28 12:27:37.833

Aromatic stacked salt bridges are increasingly observed to play an important role in biology, suggesting that the two separate weak interactions cooperate with each other to mediate molecular recognition in a biological solution. In this thesis an in depth study was carried out in attempt to find the contribution of the guanidinium-carboxylate-aromatic triad in biological systems. Two different small molecule systems are used to carry out the study. From the results of the two chapters I proposed here that stacking aromatic ring enhances the salt bridge through desolvation effect. This hypothesis was also tested in a protein-protein interaction (Grb2 SH3 domain/SOS interaction). The most ideal peptide inhibitor cannot be obtained due to the synthetic difficulties. Limited result showed that increasing the hydrophobic area of the hot spot in this protein-protein interaction enhances the interaction. In researching the guanidinium-carboxylate-aromatic triad, we were inspired to study the pre-organization effect of 1,3,5-triethyl-2,4,6-trisubstituted benzene template. A computational and literature study done in this thesis showed that the installation of ethyl or methyl groups at 1,3,5 positions leads to consistent increases in binding affinity relative to unsubstituted hosts, but the amount of increase is non-trivial and varies with different substitutes. The installation of ethyl or methyl groups at 1,3,5 positions leads to consistent but relatively small increases in binding affinity relative to unsubstituted hosts. / Graduate

The recognition of modified amino acids by reader proteins is governed by the competing interplay of weak, attractive, intermolecular forces and solvation effects. For the recognition of hydrophobic cations like methyl-lysines and methyl-arginines, native reader proteins utilize structural cages always containing multiple aromatic amino acids and sometimes an occasional acidic residue. Through the highly ordered arrangement of multiple aromatic surfaces, reader proteins can invoke the attractive forces of electrostatic, cation-pi, and in the case of arginine, pi-pi interactions. The hydrophobic effect can also significantly affect these binding events in aqueous environments. In this thesis, a number of small molecule, synthetic cages containing significant aromatic surface area have been synthesized. Variation in both total host hydrophobicity and degree of flexibility were explored to determine what effect they have on the overall binding of methylated amino acids in water. Significant flexibility in the first generation of highly aromatic hosts was shown to be detrimental to binding. However, strong binding was observed for guests with significant hydrophobic character despite this flexibility. The cause of the strong affinities in this family of synthetic cages was shown to be due to the hydrophobic effect, rather than any attraction due to cation-pi interactions. Synthetic efforts towards hosts with more rigid structures led to the use of Tröger’s base as a structural building block. Hosts incorporating Tröger’s bases into well-defined aromatic cavities were found to exhibit strong binding to both methyl-lysine and methyl-arginine derivatives in pure water. Differences in guest selectivity were due to the rigid altered host geometry introduced by the Tröger’s base cleft. / Graduate

This thesis covers the combination of two seperate work accomplished during the throughout the study. In the first part of the study, xanthene based artificial enzymes were synthesized, and kinetic hydrolysis studies done. Artificial enzyme design is an active field of supramolecular chemistry and metalloenzymes are attractive targets in such studies. Enzymatic catalysis is essentially a &lsquo / multifuctional&rsquo / catalysis. As part of our work, we designed and synthesized three novel xanthene derivatives. All three model contain Zn(II) in their active sites. Using the model substrate p-nitrophenyl acetate, we showed that the bifunctional model is at least an order of magnitude more active in catalyzing the hydrolysis of the substrate. Compared to the uncatalyzed hydrolysis reaction of the p-nitrophenyl ester at pH 7.0, the bifunctional model complex showed a 5714-fold rate acceleration. The second part of the thesis involves the design of a dimeric calixpyrrole as a chromogenic chemosensor. Anions are involved in a large number of biological processes and there is an interest in developing molecular sensors for these charged species. The calixpyrroles are a class of old but new heterocalixarene analogues that show considerable promise in the area of anion sensing. In this work, we have designed, synthesized and characterized a calixpyrrole-dimer anion sensor for its anion binding strength. The dimer forms stable complexes with p-nitrophenolate ion. This formed complex is used as a colorimetric sensor by displacing the chromogenic anion with the addition of various anions. like fluoride and acetate. The receptor shows strong affinity and high selectivity for fluoride anion, and also show reasonable affinity toward acetate. Thus, effective optical sensing of biochemically relevant these anions is accomplished using the calixpyrrole dimer.

This thesis describes research based on synthetic protocols, methodologies, and applications of polymers containing side-chain molecular recognition elements. The use of molecular recognition, in lieu of covalent chemistry, potentially presents a path through the current limits of polymer science. The work described in this thesis is, at least in part, a testament to this proposal. The first two chapters presen a basic introduction of noncovalent interactions that are ubiquitous in the research of supramolecular polymers. Chapter 2 lays the foundation for the remaining chapters of this thesis by presenting several examples of prior work related specifically to the use of molecular recognition on the side-chains of polymers. The next two chapters present research focused on advancing the functionalization of polymers through molecular recognition. These chapters demonstrate that both architecturally controlled block copolymers and random terpolymers can accept a full load of different substrates without interference among distinct molecular recognition elements along the polymer backbone. Chapters 5 and 6 present a unique application of polymers containing molecular recognition elements, templated synthesis. Chapter 5 first discusses lessons learned from small molecule based templated synthesis in which a template and a substrate are held together by metal coordination and a subsequent bond forming reaction occurs. Chapter 6 discusses template polymerizations, in which a polymeric template was used, and a daughter monomer was polymerized while attached to the template. Another application of polymers containing molecular recognition elements is presented in Chapters 7 and 8. In these chapters, metal coordination is used to assemble polymer multilayer thin films that are both responsive to external stimuli, stable, and erasable. Finally, Chapter 9 summarizes the main conclusions of each chapter and presents a potential view of new projects that might result from the research presented in this thesis.

The thesis topic entitled above involves the use of small molecules as a general means to drive nucleic acid assembly and structural transitions. We have shown that coralyne, a crescent-shaped small molecule, can assemble homo-adenine DNA and RNA sequences into anti-parallel duplexes at neutral pH, a structure containing putative purine-purine (A*A) base pairs that is otherwise unstable. The importance of the structure of the small molecule in the recognition and stabilization of A*A base pairing has been established by experimental evidence. We further provide structural evidence for the putative A*A base pairing that is stabilized by coralyne and molecules of similar size and shape. Our hypothesis that planar molecules that are slightly too large to intercalate Watson-Crick base pairs might intercalate the larger purine-purine base pairs has led to the design of a new class of small molecules that tightly bind purine-purine duplexes with excellent selectively. We have demonstrated that azacyanines can exhibit strong and selective association with a human telomeric sequence that forms a unimolecular G-quadruplex in solution. The synthetic accessibility of azacyanines makes this class of molecules amenable to library preparation for high-throughput screening. Together, the findings reported in this thesis provide further evidence for the robust and versatile nature of selective small molecule recognition of nucleic acids, especially purine-purine duplexes.

This thesis describes the preparation and characterisation of a number of homochiral coordination and metallosupramolecular assemblies. These species were formed from the reaction of chiral pyridine and quinoline containing ligands and metal ions. The combination of traditional coordination chemistry and supramolecular interactions led to a range of polymeric and network structures being formed. The ligands used in this thesis can be divided into two broad categories: alkaloids and ligands derived from them, and amino acid-based ligands. In the first category three new ligands were synthesized, and a variety of routes towards alkaloid-based homochiral ligands were investigated. The second category focused on three ligand motifs, and resulted in the preparation of 16 ligands. These two categories of ligands were reacted with a range of metal salts to investigate their coordination and supramolecular chemistry. The structure of twenty complexes was determined by single crystal X-ray crystallography. The complexes had a range of structures, with discrete and polymeric species being formed. Hydrogen bonding was an important feature in the supramolecular chemistry of the complexes, playing a different role in different series of complexes. Two chiral coordination polymers and one chiral coordination network were synthesized. All three of these structures possessed directionality to some degree: in the coordination network and one of the polymers the directionality is counterbalanced by the opposite directionality being present in the crystal, while the second coordination polymer is generated by the screw axis present and has a high degree of overall directionality.

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The main focus of this thesis is on photochemical modulation of molecular recognition in various host-guest systems. This involves the design, synthesis and integration of light-triggered conformational switches into peptidomimetic guests and molecular tweezer hosts. The impact of the switches on guest and host structures has been assessed by spectroscopic and computational conformational analysis. Effects of photochemical structure modulation on molecular recognition in protein-ligand and supramolecular host-guest systems are discussed. Phototriggerable peptidomimetic inhibitors of the enzyme M. tuberculosis ribonucleotide reductase (RNR) were obtained by incorporation of a stilbene based amino acid moiety into oligopeptides between 3-9 residues long (Paper I). Interstrand hydrogen bond probability in the E and Z forms of the peptidomimetics was used as a tool for predicting conformational preferences. Considerable differences in inhibitory potency for the E and Z photoisomers were demonstrated in a binding assay. In order to advance the concept of photomodulable inhibitors, synthetic routes towards amino acid derivatives based on the more rigid stiff-stilbene chromophore were developed (Paper II).  The effect of E-Z isomerization on the conformational properties of peptidomimetic inhibitors incorporating the stiff-stilbene chromophore was also assessed computationally (Paper III). It was indicated that inhibitors with the more rigid amino acid derivative should display larger conformational divergence between photoisomers than corresponding stilbene derivatives. Bisporphyrin tweezers with enediyne and stiff-stilbene spacers have been synthesized, and the conformational characteristics imposed by the spacers have been studied and compared to a glycoluril linked tweezer. The effects of spacers on tweezer binding of diamine guests and helicity induction by chiral guests have been investigated (Paper IV). Connections between spacer flexibility and host-guest binding strength have been established. The structural properties of the stiff-stilbene spaced tweezer made it particularly susceptible to helicity induction by both monotopic and bitopic chiral guests. Finally, the possibility of photochemical bite-size variation of tweezers with photoswitchable spacers has been assessed. Initial studies have shown that photoisomerization of the tweezers is possible without photochemical decomposition. Conformational analyses indicate that isomerization should impact binding characteristics of the tweezers to a significant extent (Paper V).

xxi, 172 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / Main group supramolecular chemistry is a rapidly expanding field that combines the tools of coordination chemistry with the unusual and frequently unexpected coordination preferences exhibited by the main group elements. Application of established supramolecular design principles to those elements provides access to novel structure types and the possibility of new functionality introduced by the rich chemistry of the main group. Chapter I is a general review of the field of main group supramolecular chemistry, focusing in particular on the aspects of coordination chemistry and rational design strategies that have been thus far used to prepare polynuclear "metal"-ligand assemblies. Chapter II is a discussion of work toward supramolecular assemblies based on the coordination preferences of lead(II), in particular focusing on the 2-mercaptoacetamide and arylthiolate functionalities to target four-coordinate and three-coordinate geometries, respectively. Several possible avenues for further pursuing this research are suggested, with designs for ligands that may provide a more fruitful approach to the coordination of lead(II). Chapter III deals with the preparation of As 2 L 3 assemblies based on flexible ligand scaffolds. These assemblies exhibit structural changes in response to temperature and solvent, which may provide some insight into the subtle shape requirements involved in supramolecular guest binding. Chapter IV continues this work with an examination of how ligand structure affects mechanical coupling of stereochemistry between metal centers when the chelate ring is completed by a secondary bonding interaction such as the As-π contact. Finally, Chapter V presents a crystallographic and synthetic study of the nature of the interaction between pnictogens and arene rings. This interaction is ubiquitous in the coordination chemistry performed in the Johnson laboratory; understanding the role these interactions play in determining the final structure of supramolecular assemblies is vital to the preparation of more complex structures. Chapter VI presents a set of conclusions and outlook for future work on lead(II) supramolecular assemblies and the dynamic assemblies prepared from flexible organic scaffolds. This dissertation contains previously published and coauthored material. / Committee in charge: Kenneth Doxsee, Chairperson, Chemistry; Darren Johnson, Advisor, Chemistry; David Tyler, Member, Chemistry; Victoria DeRose, Member, Chemistry; Stephen Remington, Outside Member, Physics