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Improved methodology for the synthesis of bicycle octapeptides

University of British Columbia

Rigidity is an important property of drugs and small molecule toxins that enhances the affinity for their targets. Amatoxins are highly rigid bicyclic peptides that bind to and consequently inhibit RNA Polymerase II. In this thesis we present an improved methodology for the synthesis of a tryptathionine linkage, which constitutes the rigidifying bridge that is a distinguishing feature of amatoxins and related phallotoxins. The Savige-Fontana reaction was used to form 3ahydroxyhexahydropyrroloindoles (Hpi), critical intermediates for substitution at the 2- position of the tryptophan indole. Our strategy consisted of forming Hpi as a dipeptide by oxidizing with dimethyldioxirane various Tr-Trp-X-OMe compounds (with X=Ser, Val, Lys(Boc), Leu). Good yields were obtained (75 - 92%), except for leucine due to concurrent side-chain oxidation. Our strategy was applied to the inter- or intramolecular formation of a linkage between cysteine and tryptophan, which gave rise to compounds 2, 3 and 4 and finally to the synthesis of the amatoxin Pro2,lle3-deoxo-amaninamide 1. After formation of the linear octapeptide Tr-Hpi-Gly-lle-Gly-Cys(Tr)-Asn(Tr)-Pro-lle-OtBu using the "rapid continuous peptide synthesis" method, TFA treatment gave rise to the corresponding unprotected monocyclic peptide 64 bearing a tryptathionine bridge. A macrolactamization with PyBOP as coupling reagent gave rise to a mixture of the target 1 and its inactive atropisomer. Compound 1 was isolated and characterized.

Thesis/Dissertation

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2009-11-21

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http://hdl.handle.net/2429/15421

Chemistry

University of British Columbia

UBCV

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