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Synthesis, characterisation, and in vitro evaluation of Pro(2)-Ile(3)-S-deoxo-amaninamide and Pro(2)-D-allo-Ile(3)-S-deoxo-amaninamide: Implications for structure-activity relationships in amanitin conformation and toxicity

TitleSynthesis, characterisation, and in vitro evaluation of Pro(2)-Ile(3)-S-deoxo-amaninamide and Pro(2)-D-allo-Ile(3)-S-deoxo-amaninamide: Implications for structure-activity relationships in amanitin conformation and toxicity
Publication TypeJournal Article
Year of Publication2008
AuthorsMay, JP, Fournier, P, Patrick, BO, Perrin, DM
JournalChemistry-a European Journal
Volume14
Pagination3410-3417
Type of ArticleArticle
ISBN Number0947-6539
KeywordsALPHA-AMANITIN, amatoxin, atropisomerism, circular dichroism, CRYSTALLINE STATE, CYCLIZATION, CYSTEINE SULFHYDRYL-GROUPS, EPIMERIZATION, MOLECULAR-STRUCTURE, PEPTIDES, RESOLUTION, RNA-POLYMERASE-II, SERIES, TOXIN BETA-AMANITIN, transcription
Abstract

The amatoxins are a family of toxic bicyclic peptides that inhibit RNA polymerase II. Herein we discuss an improved synthesis of these compounds from easily obtainable amino acids by means of a solid-phase methodology. Interestingly, we obtained two products of the same mass following our final macrocyclisation, relating to a similar distribution of products described in some previous reports. One of these products was the desired amatoxin; Pro(2)-Ile(3)-S-deoxo-amaninamide 1b. The other compound, after thorough investigation, was confirmed to be the epimer Pro(2)-D-allo-Ile(3)-S-deoxo-amaninamide la, not an atropisomer structure as previously suggested in syntheses of related amanitin analogues. Crystallographic data of la confirms the presence of a beta II-turn, rather than a PI-turn common to the natural toxin and 1b. This difference explains the large variation in CD spectra, although it seems to have relatively little effect on the bioactivity in vitro. These data provide new insights into the bicyclic amatoxin structure.

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