A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues

The
highly cytotoxic cyclodepsipeptides of the nannocystin family are
known to bind to the eukaryotic translation elongation factor 1α
(EF-1α). Analysis of the docking pose, as proposed by a previous
in silico study, suggested that the trisubstituted alkene moiety and
the neighboring methyl ether form a domain that might be closely correlated
with biological activity. This hypothesis sponsored a synthetic campaign
which was designed to be “motif-oriented”: specifically,
a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived,
which allowed this potentially anchoring substructure to be systematically
addressed at a late stage. This inherently flexible approach opened
access to nannocystin Ax (1) itself as well as to 10
non-natural analogues. While the biological data confirmed the remarkable
potency of this class of compounds and showed that the domain in question
is indeed an innate part of the pharmacophore, the specific structure/activity
relationships can only partly be reconciled with the original in silico
docking study; therefore, we conclude that this model needs to be
carefully revisited.