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By replacement of an acetate with propionate through organic synthesis a range of zearalenone analogues were prepared. As key steps in the synthesis of the analogues we used the Noyori hydrogenation of methyl acetoacetate followed by Frater alkylation of the enantiomeric 3-hydroxybutyrates. This converted the second acetate to a propionate. Through the derived alkyne, chain extension led to 3-methylundec-10-en-2-ol derivatives. These were condensed with 2,4-dimethoxy-6-vinylbenzoic acid. Ring-closing metathesis of the obtained esters led to macrolactones, which were deproteced to give the zearalenone analogues. Several of the analogues showed cytotoxicity against the L929 mouse fibroblast cell line comparable to zearalenone (9 microM) itself. In the thermal-shift assay, two analogues 35 and ent-35 displayed stronger binding than the natural product geldanamycin to the chaperone Hsp90.

Original publication

DOI

10.1002/cbic.200900109

Type

Journal article

Journal

Chembiochem

Publication Date

04/09/2009

Volume

10

Pages

2203 - 2212

Keywords

Animals, Cell Line, HSP90 Heat-Shock Proteins, Hydrogenation, Ligands, Macrolides, Mice, Propionates, Protein Binding, Stereoisomerism, Zearalenone