For
70 years, α-amanitin, the most cytotoxic peptide in its
class, has been without a synthetic rival; through synthesis, we address
the structure–activity relationships to inform the design of
new amatoxins and disclose analogues that are more cytotoxic than
the natural product when evaluated on CHO, HEK293, and HeLa cells,
whereas on liver-derived HepG2 cells, the same toxins show diminished
cytotoxicity.