Functional Behavior of Molecular Baskets and Structure-Activity Studies on Trapping Organophosphorus Nerve Agents in Water

Molecular recognition is exploited by nature to carry out delicately regulated reactions and form precisely organized structures in living organisms. Enzymes promote reactions by preorganizing substrates and stabilizing transition states in an active site via covalent and non-covalent interactions. Receptor proteins and antibodies can respond selectively to stimuli and trigger subsequent activities. These protein-substrate interactions have been great inspirations for chemists in the design of synthetic receptors as hosts and the study of their molecular recognition properties. Investigation of recognition behaviors can help decipher sub-cellular processes. Moreover, some artificial host-guest complexes have found applications in catalysis, sensing, imaging and drug delivery systems.;The Badjic group has developed a family of host molecules called molecular baskets to study the effect of gating on molecular recognition. These baskets possess a cavity formed by a benzene base and phthalimide side walls. Pyridine-based gates close the basket via hydrogen bonds or metal chelation. Tuning the electronic and steric characteristics of gates affects the rate of guests entering and departing the basket.;With all the knowledge about molecular gating, questions arise as to whether these gates can be applied to other platforms and how the mechanism of gating will be affected. A new quinoxaline containing platform was synthesized, which gave a more spacious basket 2.1 (see Chapter 2). Amidopyridine gates were installed and shown to close the basket by forming a seam of intramolecular hydrogen bonds. The recognition characteristics of both smaller basket 1.7 and bigger 2.1 were quantified in different solvents and the apparent guest binding (Ka) was found to be inversely proportional to the affinity of bulk solvents populating each host (Ks). Mechanisms of gate operations were also investigated for both baskets. Results suggested two competing pathways, determined by the population of basket&;All previous recognition studies of molecular basket were carried out in organic solvents; however, creating similar hosts in aqueous media is desirable, as water is the media for all biological reactions. Water-soluble synthetic receptors are excellent tools to study more complicated processes in nature. In an effort to mimic butyrylcholinesterase (BuChE) and paraoxonase-1 (PON1) enzymes as bioscavengers of organophosphorus compounds, water soluble cup-shaped basket 3.1 was developed. The basket with histamine residues (see Chapter 3) was first prepared and is able to trap organophosphonates whose shape and size correspond to chemical warfare agents of G type. A series of organophosphonates were found to bind the basket with different affinities. Experimental and computational studies indicated that the cavity can expand to accommodate more sizable guests, suggesting an induced-fit model of recognition.;Subsequently, baskets 4.1--4.7 with amino acids at the rim (see Chapter 4) were synthesized and solubilized in water at physiological pH. They were found to trap dimethyl methylphosphonate (DMMP), akin to sarin in size, and steric interactions at the rim had a great impact on the binding affinity. These results are important toward creating effective supramolecular sensors and degradation catalysts of nerve agents.