Total Synthesis of α- and β-Amanitin

Angew Chem Int Ed Engl. 2020 Jul 6;59(28):11390-11393. doi: 10.1002/anie.201914935. Epub 2020 Apr 28.

Abstract

α-Amanitin and related amatoxins have been studied for more than six decades mostly by isolation from death cap mushrooms. The total synthesis, however, remained challenging due to unique structural features. α-Amanitin is a potent inhibitor of RNA polymerase II. Interrupting the basic transcription processes of eukaryotes leads to apoptosis of the cell. This unique mechanism makes the toxin an ideal payload for antibody-drug conjugates (ADCs). Only microgram quantities of toxins, when delivered selectively to tumor sites through conjugation to antibodies, are sufficient to eliminate malignant tumor cells of almost every origin. By solving the stereoselective access to dihydroxyisoleucine, a photochemical synthesis of the tryptathion precursor, solid-phase peptide synthesis, and macrolactamization we obtained a scalable synthetic route towards synthetic α-amanitin. This makes α-amanitin and derivatives now accessible for the development of new ADCs.

Keywords: amanitins; amino acids; peptides; solid-phase synthesis; total synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agaricales / chemistry
  • Alpha-Amanitin / chemical synthesis*
  • Alpha-Amanitin / chemistry
  • Amanitins / chemical synthesis*
  • Amanitins / chemistry
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Cyclization
  • Immunoconjugates
  • Proton Magnetic Resonance Spectroscopy

Substances

  • Alpha-Amanitin
  • Amanitins
  • Immunoconjugates
  • beta-amanitin