Synthesis, characterisation, and in vitro evaluation of Pro2-Ile3-S-deoxo-amaninamide and Pro2-D-allo-Ile3-S-deoxo-amaninamide: implications for structure-activity relationships in amanitin conformation and toxicity.
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 1 b. The other compound, after thorough investigation, was confirmed to be the epimer Pro(2)-D-allo-Ile(3)-S-deoxo-amaninamide 1 a, not an atropisomer structure as previously suggested in syntheses of related amanitin analogues. Crystallographic data of 1 a confirms the presence of a betaII-turn, rather than a betaI-turn common to the natural toxin and 1 b. 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.
May
Jonathan P
JP
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada.
Fournier
Pierre
P
Patrick
Brian O
BO
Perrin
David M
DM
D053959:Alpha-Amanitin / Q000737:chemistry* / Q000633:toxicity*; D000546:Amanitins / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D053959:Alpha-Amanitin; D000546:Amanitins; C023518:amaninamide