title: Anguinomycins and derivatives: total syntheses, modeling, and biological evaluation of the inhibition of nucleocytoplasmic transport.
abstract: The preparation of the polyketide natural products anguinomycin C and D is reported based on key steps such as Negishi stereoinversion cross coupling, Jacobsen Cr(III)-catalyzed Hetero Diels-Alder reaction, Evans B-mediated syn-aldol chemistry, and B-alkyl Suzuki-Miyaura cross coupling. The configuration of both natural products was established as (5R,10R,16R,18S,19R,20S). Biological evaluation demonstrated that these natural products are inhibitors of the nuclear export receptor CRM1, leading to shutdown of CRM1-mediated nuclear protein export at concentrations above 10 nM. Analogues of anguinomycin and leptomycin B (LMB) have been prepared, and the simple alpha,beta-unsaturated lactone analogue 4 with a truncated polyketide chain retains most of the biological activity (inhibition above 25 nM). The structural basis for this inhibition has been demonstrated by modeling the transport inhibitors into X-ray crystal structures, thus highlighting key points for successful and strong biological action of anguinomycin and LMB.
authors.affiliation: Chemical Synthesis Laboratory (SB-ISIC-LSYNC), Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Bonazzi
authors.forename: Oliv
authors.initials: O
authors.lastname: Eidam
authors.forename: Stephan
authors.initials: S
authors.lastname: Güttinger
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Wach
authors.forename: Ivo
authors.initials: I
authors.lastname: Zemp
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kutay
authors.forename: Karl
authors.initials: K
authors.lastname: Gademann
mesh_terms: D001692:Biological Transport / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C096621:anguinomycin C; C096622:anguinomycin D