Meeting key synthetic challenges in amanitin synthesis with a new cytotoxic analog: 5′-hydroxy-6′-deoxy-amanitin

Abstract

Elucidating a highly diastereoselective sulfoxidation of S-deoxy-amanitin to afford α-amanitin and a more synthetically accessible analog of near-native toxicity.

Design, Synthesis, and Biochemical Evaluation of Alpha‐Amanitin Derivatives Containing Analogs of thetrans‐Hydroxyproline Residue for Potential Use in Antibody‐Drug Conjugates

“…We based our analysis on the synthetically more accessible “dideoxy‐amanitin” ( sic 6′‐deoxy‐S‐deoxo‐α‐amanitin) ( 2 ) lacking both the 6′‐OH and the ( R )‐sulfoxide, where the thioether is known to be equipotent in cytotoxicity assays, [13,19] confirmed by us and others [9d,17,20] . Typically, toxins constructed with a simple tryptathionine staple show near‐native potencies [2a,14a,21] .…”

Synthesis and preliminary evaluation of octreotate conjugates of bioactive synthetic amatoxins for targeting somatostatin receptor (sstr2) expressing cells

“…To expand the potential for new amanitin derivatives, we recently reported the synthesis of an unnatural 5'-hydroxy-6'-deoxy-amanitin (3) that is equipotent to αamanitin (along with the corresponding (R)-sulfoxide, and the sulfone). 52 With this more synthetically accessible toxin in hand, here we report on conjugates that would exploit the 5'-hydroxy-6'-deoxy-amanitin 3 (Figure 2B). We further expand this study on octreotate conjugates to include conjugation to N-propargyldideoxy-amanitin 4 (Figure 2B), 33 an alternative, equally synthetically accessible derivative that lacks the 6'hydroxyindole yet shows near-native toxicity (IC50 on CHO cells 1-2 µM compared to 0.3-0.7 µM for α-amanitin) and is equipped with an alkyne conjugation handle for copper(I)-catalyzed azidealkyne cycloaddition (CuAAC).…”

“…In the context of grafting to the tryptathionine staple, we noted antecedent reports of amanitin-RGD peptide conjugates linked to the 6'-hydroxyl group in amanitin. 31 Following our recent report on the more synthetically accessible 5'hydroxytryptathionine-stapled amanitin, 52 we took advantage of the nucleophilicity of the 5'-hydroxyl group for grafting linkers to the 5'-hydroxytrypthathionine as well. Towards this end, we appreciated the recent success of valine-citrulline (Val-Cit) Cathepsin B cleavable linkers in FDA approved ADCs.…”

Iodine-Mediated Tryptathionine Formation Facilitates the Synthesis of Amanitins

“…Then the benzyl protecting group of S27 was cleaved with BF 3 –Et 2 O. The final stereoselective oxidation of tryptathionine to the tryptathionine sulfoxide followed Perrin’s recent work on this step , thus rendering α-amanitin, which was purified by preparative HPLC (see Supporting Information Scheme S10). The 1 H and 2D NMR spectra were fully consistent with those of natural α-amanitin (for comparison of NMR spectra, see Supporting Information, Figure S11 and Figure S12).…”