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Synthesis on solid phase of a bicyclic octapeptide amatoxin

University of British Columbia

The α-amanitin is an excellent template for use in the design of a chemical library on solid phase in order to study the mechanisms involved in the regulation of transcription. Indeed, α-amanitin selectively inhibits with high affinity the RNA Polymerase II. The α-amanitin belongs to the amatoxin family which is characterized by a defined rigid bicyclic structure consisting of a head-to-tail cyclized octapeptide, with a transannular linkage known as a tryptathionine bridge. The latter is made via the Savige-Fontana tryptathionylation of the oxidized tryptophan derivative 3α-hydroxypyrrolo[2,3-b]indoline in neat TFA. Therefore, in order to achieve the synthesis of an α-amanitin-based library on solid phase, the linker must be stable both in TFA and during the peptide synthesis. Such a linker was found in the tartrate-based linker. As proof of this concept, following completion of the linker synthesis on solid phase, the linear octapeptide precursor of Pro²-Glu³-S-deoxo-amaninamide was prepared by standard Fmoc/tert-Bu SPPS. The tryptathionine bridge was achieved by the Savige-Fontana reaction and the second cyclization was performed by a head-to-tail macrolactamization, all on PEGA resin. The bicyclic octapeptide was cleaved off from the linker with the mild sodium periodate oxidant, purified by RP-HPLC and characterized by HRMS (ESI) and UV spectra.

Thesis/Dissertation

application/pdf

2009-08-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/12343

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/