lemonomycin and goniothalamin

An in vivo nuclear export assay (immunostaining of Rio2 in HeLa cells) demonstrated that (R)-goniothalamin is an inhibitor of nucleocytoplasmic transport above 500 nM, which was rationalized also by molecular modeling. The cytotoxic styryl lactone natural product was prepared via an enantioselective Cr(III) catalyzed hetero Diels-Alder reaction and a Sonogashira coupling. A series of analogs was synthesized and only the oxidized goniothalamin derivative featuring an alkyne spacer was found active. Unsaturated lactones of natural origin other than leptomycin (LMB) are thus suggested to operate via a similar mechanism targeting the CRM1 nuclear receptor.

Topics: Active Transport, Cell Nucleus; Binding Sites; Catalysis; Cell Nucleus; Chromium; Computer Simulation; Crystallography, X-Ray; HeLa Cells; Humans; Lactones; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrones; Stereoisomerism; Tetrahydroisoquinolines