Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide

It
was by way of total synthesis that the issues concerning the
stereostructure of leiodermatolide (1) have recently
been solved; with the target now being unambiguously defined, the
mission of synthesis changes as to secure a meaningful supply of this
exceedingly scarce natural product derived from a deep-sea sponge.
To this end, a scalable route of 19 steps (longest linear sequence)
has been developed, which features a catalytic asymmetric propargylation
of a highly enolizable β-keto-lactone, a ring closing alkyne
metathesis and a modified Stille coupling as the key transformations.
Deliberate digression from this robust blueprint brought a first set
of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays,
distinguished by GI50 values in the ≤3 nM range
even for cell lines expressing the Pgp efflux transporter. Studies
with human U2OS cells revealed that 1 causes mitotic
arrest, micronucleus induction, centrosome amplification and tubulin
disruption, even though no evidence for direct tubulin binding has
been found in cell-free assays; moreover, the compound does not seem
to act through kinase inhibition. Indirect evidence points at centrosome
declustering as a possible mechanism of action, which provides a potentially
rewarding outlook in that centrosome declustering agents hold promise
of being inherently selective for malignant over healthy human tissue.