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Toward the preparation of a directed library of amatoxins containing modified prolines Pellicelli, Jonathan

Abstract

Amatoxins are bicyclic peptides found in the Amanita mushroom species; these molecules are specific inhibitors of RNA polymerase II. Crystal structure data for the amatoxin-RNA polymerase II complex suggest that the hydrogen bond between Pol II Glu882 and amatoxin hydroxyproline is the key interaction in the binding of amatoxins to Pol II. We decided to synthesize a small library of amatoxins that will investigate this suspected key interaction. The amatoxins in this library contain modified prolines which represent analogue of hydroxyproline. The formation of the library was achieved in three synthetic phases. The first phase of the project was the synthesis of the various proline derivatives chosen to be incorporated into amatoxin peptides. These prolines were fluoroproline, difluoroproline, trifluoromethylproline, cyanoproline, benzylthioproline, azidoproline, hydroxyproline, ketoproline, and thiazolidine acid. The second phase of the project was the synthesis of 3a-hydroxyhexahydropyrroloindoles (Hpi). This molecule is essential for the formation of the tryptathionine bridge (a key feature in the amatoxin molecule) via a Savige-Fontana reaction. The last phase of the project was the formation of linear octapeptides and their subsequent cyc1ization. Seven linear octapeptides and two monocyc1ic octapeptides were prepared.

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