Anguinomycins and derivatives: total syntheses, modeling, and biological evaluation of the inhibition of nucleocytoplasmic transport.
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.
Bonazzi
Simone
S
Chemical Synthesis Laboratory (SB-ISIC-LSYNC), Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
Eidam
Oliv
O
Güttinger
Stephan
S
Wach
Jean-Yves
JY
Zemp
Ivo
I
Kutay
Ulrike
U
Gademann
Karl
K
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
D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C096621:anguinomycin C; C096622:anguinomycin D