The polyene pyrone mycotoxins (citreoviridin, asteltoxin, and aurovertin B) are toxic molecules which are known to bind to and inhibit F1-ATP synthetase, a key enzyme in the process of oxidative phosphorylation. These molecules are not readily available, and a supply of synthetic analogs which have similar inhibitory and fluorescent properties would be of value in investigations probing the mechanisms of oxidative phosphorylation. This project is designed to develop and test techniques for the preparation of synthetic analogs of the polyene pyrone mycotoxins. The naturally occurring toxins contain saturated furanoid and pyranoid rings. A new process for preparing analogous rings from carbohydrate precursors has been developed, and refinements and extensions of this technique will be sought. The natural toxins may be considered to be derivatives of 6-alkenyl-4-methoxy-5-methyl-2-pyrones. A careful evaluation of synthetic approaches to such pyrone derivatives will be carried out. Several molecules which could be expected to have inhibitory properties will be prepared as a result of these evaluations. The synthesis of citreoviridin, the simplest of the polyene pyrone toxins will be completed in order to demonstrate the practicality of these techniques. Intermediates and analogs will be tested. The long term goals of this project include the determination of necessary and sufficient structural requirements for inhibition, and the development of practical methods for the total synthesis of active analogs of these toxic natural products.
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