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

Abstract

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.

Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity

“…If leiodermatolide binds tubulin, it does it at a different stoichiometry than the observed 1:1 for compounds such as paclitaxel . A recent publication has confirmed our observation that leiodermatolide does not directly bind tubulin …”

“…Studies to try to determine its mechanism of action and molecular target of leiodermatolide continue, but the data to date suggests that the mechanism of action of leiodermatolide may differ from other tubulin interacting compounds. A similar conclusion was reached by the Fürstner group who studied the effects of synthetic leiodermatolide on the U2OS osteosarcoma cell line . They found that leiodermatolide does not directly bind tubulin, that its effects on cell cycle arrest and cytotoxicity are similar to other tubulin interacting compounds without in vitro effects on tubulin and they postulated centrosome declustering as a possible mechanism of action for leiodermatolide with further studies needed to confirm this potential mechanism of action .…”

Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

“…Cell‐cycle arrest occurred at the G2/M phase, accompanied by abnormal mitotic spindle formation, a characteristic response to anticancer agents that interact with tubulin (e.g., taxol, discodermolide, dictyostatin) . The mechanism of action was independently investigated at Pfizer, working with synthetic material made available from the Fürstner group . These studies revealed several unusual, concentration‐dependant effects, not previously observed for microtubule‐targeting agents.…”

“…Correlation of the optical rotation also confirmed that structure 5 represents the natural enantiomer. Subsequently, the Fürstner group reported an improved synthesis of (−)‐leiodermatolide, along with further biological results …”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…Construction of a cyclic alkyne-bis(lactone) system was a key event in the synthesis of oxygenated metabolites of n-3 polyunsaturated fatty acids [1331]. Ring closing alkyne metathesis using a conjugated enyne (1570) substrate was employed for a scalable total synthesis of leiodermatolide and leiodermatolide analogs [1332,1333]. Formation of a macrocycle-bridged biphenyl system (e.g.…”