In recent years, a major goal in the field of artificial receptors has been the development of molecular machines capable of catalyzing organic reactions. The hydrolysis of organophosphates is of particular importance due to the dangers these compounds present. Organophosphates such as paraoxon, VX and sarin are highly toxic because only one molecule is required to inhibit serine hydrolaces such as acetylcholinesterace (AChE) and butyrylcholinesterace (BChE). Current treatments against exposure to theses compounds are only mildly effective. Our over all goal is to create novel artificial receptors, host-rotaxanes, capable of binding and hydrolyzing organophosphates before they can inhibit enzyme activity.
A new synthetic reagent, DCC-rotaxane, was developed for producing rotaxanes. Utilizing template driven synthetic techniques dibenzo-24-crown-8 ether was non-covalently threaded over an amino acid tether. Binding constants for various length amino acid tethers were determined via 1H NMR titration experiments. Rotaxane formation reactions demonstrated a tether with 4 methylenes between the amine and carboxylic acid produced rotaxane in a 73% yield.
A host-rotaxane was designed as an enzyme mimetic incorporating three key elements: specific substrate recognition, transition state stabilization and product release. The host-rotaxane is unique from previous artificial receptor because the catalytic functionality is fixed upon a free-sliding crown ether simulating the catalytic motion observed in enzymes. Utilizing the DCC-rotaxane, the first host-rotaxanes were produced. Initial 1H NMR titration and UV / Vis spectroscopic experiments demonstrated association constants were too high to measure in the 10-4 M concentration range. At lower concentration ranges it was necessary to incorporate a fluorophore into the host-rotaxane system.
Modifications were made to the DCC-rotaxane reagent so various different fluorophores can be easily attached. An extensive library of modified tethers were synthesized and screened for rotaxane forming ability. By introducing an azide functional group into the tether, we were able to attach fluorescein while maintaining high rotaxane yields. Fluorescent studies of model fluorescent rotaxanes at 10-9 M in water demonstrated derivatized crown ethers quenched fluorescence by 90%. Based on these encouraging results, host-rotaxanes can be designed for use as chemical sensors in various applications.
|Advisor:||Smithrud, David B.|
|School:||University of Cincinnati|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Fluorescence, Host-guest, Molecular machine, Rotaxane, Template driven synthesis|
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