Total synthesis and biological evaluation of rakicidin A and discovery of a simplified bioactive analogue
| Autor: | Eva S. Schaffert, Thomas B. Poulsen, Lise L. Clement, Michail Tsakos, Kristian M. Jacobsen, Frank N. Olsen, Nikolaj L. Villadsen, Wanwan Yu, Rasmus Djurhuus, Sebastiano Rupiani |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Stereochemistry
natural products 010402 general chemistry 01 natural sciences Peptides Cyclic Catalysis Coupling reaction antitumor agents Elimination reaction Polyketide Lipopeptides Cell Line Tumor Drug Discovery Molecule Humans total synthesis Depsipeptide tumor hypoxia cyclolipodepsipeptides 010405 organic chemistry Chemistry Enantioselective synthesis Total synthesis General Chemistry General Medicine Combinatorial chemistry 0104 chemical sciences Cancer cell |
| Zdroj: | Tsakos, M, Clement, L L, Schaffert, E S, Olsen, F N, Rupiani, S, Djurhuus, R, Yu, W, Jacobsen, K M, Villadsen, N L & Poulsen, T B 2016, ' Total synthesis and biological evaluation of rakicidin A and discovery of a simplified bioactive analogue ', Angewandte Chemie International Edition, vol. 55, no. 3, pp. 1030-1035 . https://doi.org/10.1002/anie.201509926 |
| DOI: | 10.1002/anie.201509926 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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