The cytotoxic styryl lactone goniothalamin is an inhibitor of nucleocytoplasmic transport.
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.
Wach
Jean-Yves
JY
Swiss Federal Institute of Technology (EPFL), Chemical Synthesis Laboratory (SB-ISIC-LSYNC), 1015 Lausanne, Switzerland.
Güttinger
Stephan
S
Kutay
Ulrike
U
Gademann
Karl
K
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D001665:Binding Sites; D002384:Catalysis; D002467:Cell Nucleus / Q000378:metabolism*; D002857:Chromium / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology
D007783:Lactones; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D044005:Tetrahydroisoquinolines; C481507:lemonomycin; D002857:Chromium; C103280:goniothalamin; D017346:Protein Serine-Threonine Kinases; C542171:RIOK2 protein, human