Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue.

Autor: Tsakos M; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Clement LL; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Schaffert ES; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Olsen FN; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Rupiani S; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Djurhuus R; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Yu W; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Jacobsen KM; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Villadsen NL; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark., Poulsen TB; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark. thpou@chem.au.dk.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2016 Jan 18; Vol. 55 (3), pp. 1030-5. Date of Electronic Publication: 2015 Dec 04.
DOI: 10.1002/anie.201509926
Abstrakt: We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.
(© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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