Amatoxins bearing amino and carboxyl groups prepared by selective alteration of the aldehyde generated by periodate oxidation of methylated α‐amanitin¹

Abstract

Amatoxins are cyclic peptides which can be purified from the carpophores of various mushroom species. Since they were first recognized as potent inhibitors of the nuclear RNA polymerases of most cukaryotes these peptides have served as important tools in the study of transcription. The presence of unusual amino acid residues in these peptides has provided opportunities to attempt a variety of semisynthetic modifications. We describe several new amatoxin derivatives that were prepared by selective modification of an aldehyde group which can be generated by periodate oxidation of 6’‐O‐methyl‐α‐amanitin. The derivatives which resulted from sodium cyanoborohydride‐mediated coupling to the toxin of ammonia, glycine, and l‐proline exhibited Ki values for calf thymus RNA polymerase II of 1.7 × 10−7m, 2.5 × 10−7m and 7.0 × 10−6m, respectively. Treatment of the aldehyde with sodium chlorite or hydroxylamine‐O‐sulfonic acid converted the amanitin aldehyde to the corresponding carboxyl or nitrile compounds with Ki values of 1.0 × 10−7m and 3.0 × 10−9m, respectively. Difficulties which were encountered in the preparation of these derivatives are discussed relative to peculiarities in the chemical behavior of the amanitin aldehyde.

Solid‐phase synthesis of amanitin derivatives and preliminary evaluation of cellular uptake and toxicity

“…Nevertheless other studies suggested that DHIle could be replaced by Ile without a significant loss of inhibition against RNAP II in vitro but may impact cell permeability . Interestingly, metaperiodate cleavage of the DHIle followed by borohydride reduction to give hydroxyvaline afforded a toxin that exhibited near‐native toxicity …”