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Anguinomycins and Derivatives: Total Syntheses, Modeling, and Biological Evaluation of the Inhibition of Nucleocytoplasmic Transport

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journal contribution
posted on 03.02.2010, 00:00 by Simone Bonazzi, Oliv Eidam, Stephan Güttinger, Jean-Yves Wach, Ivo Zemp, Ulrike Kutay, Karl Gademann
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 α,β-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.