Synthesis of Morpholine-Based Analogues of (-)-Zampanolide and Their Biological Activity.

Autor: Bold CP; Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland., Gut M; Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland., Schürmann J; Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland., Lucena-Agell D; Centro de Investigaciones Biolόgicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040, Madrid, Spain., Gertsch J; Department of Chemistry and Applied Biosciences, Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland., Díaz JF; Centro de Investigaciones Biolόgicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040, Madrid, Spain., Altmann KH; Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2021 Apr 01; Vol. 27 (19), pp. 5936-5943. Date of Electronic Publication: 2021 Mar 03.
DOI: 10.1002/chem.202003996
Abstrakt: We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (-)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino-zampanolides investigated, the N-acetyl and the N-benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N-tosyl derivative was significantly reduced.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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