title: Structure-toxicity relationships in the amatoxin series. Structural variations of side chain 3 and inhibition of RNA polymerase II.
abstract: The amatoxins, highly toxic components of death cap Amanita mushrooms, bind strongly to RNA polymerase II (or B) in cell nuclei thus preventing the transcription of DNAs to hn-RNAs (Pre-mRNAs), the precursors of messenger RNAs. Three of the binding sites of the bicyclic octapeptides have been identified: an isoleucine side chain in position 6, a trans-4-hydroxyl group at proline in position 2 and a hydroxylated L-isoleucine side chain in position 3. No information exists about the stereochemical conditions at the beta-C-atom (C-atom 3) of this side chain. We have now synthesized the diastereomeric S-deoxo-amaninamides (Fig. 1) containing, in position 3, L-allo-isoleucine (analog 1), (2S, 3R)-2-amino-4-hydroxy-3-methyl butyric acid (analog 2), the diastereomer (2S, 3S)-2-amino-4-hydroxy-3-methylbutyric acid (analog 3) and D-isoleucine (analog 4). In the last synthesis, besides the "normal" bicyclic octapeptide 4, an isomeric Iso-4 was formed. The affinities for Drosophila RNA polymerase II were 100 times weaker as compared to gamma-amanitin for 1, 10 times weaker for 2, 200 times weaker for 3, 100 times weaker for 4, and more than 1000 times weaker for Iso-4. The results point to the importance of a methyl group in (R)-configuration at the beta-C atom of side chain 3.
authors.affiliation: Department of Pharmaceutical Sciences, University La Sapienza, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zanotti
authors.forename: G
authors.initials: G
authors.lastname: Petersen
authors.forename: T
authors.initials: T
authors.lastname: Wieland
mesh_terms: D000546:Amanitins / Q000737:chemistry / Q000633:toxicity*; D000595:Amino Acid Sequence; D000818:Animals; D002942:Circular Dichroism; D004331:Drosophila melanogaster / Q000201:enzymology; D008969:Molecular Sequence Data; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000546:Amanitins; C018207:amatoxin; D012319:RNA Polymerase II