title: 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.
authors.affiliation: Max-Planck-Institut für Kohlenforschung , D-45470 Mülheim/Ruhr, Germany.
authors.forename: Damien
authors.initials: D
authors.lastname: Mailhol
authors.forename: Jens
authors.initials: J
authors.lastname: Willwacher
authors.forename: Nina
authors.initials: N
authors.lastname: Kausch-Busies
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Rubitski
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Sobol
authors.forename: Maik
authors.initials: M
authors.lastname: Schuler
authors.forename: My-Hanh
authors.initials: MH
authors.lastname: Lam
authors.forename: Sylvia
authors.initials: S
authors.lastname: Musto
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Andreas
authors.initials: A
authors.lastname: Maderna
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
mesh_terms: D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure
chemical_list: D018942:Macrolides; C559222:leiodermatolide