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In order to extend the chemical diversity available for organic polyketide synthesis, the concept of propionate scanning was developed. We observed that naturally occurring polyketides frequently comprise not only acetate, but also some propionate as building blocks. Therefore our approach consists of a systematic replacement of some of the acetate building blocks during synthesis by propionate moieties, resulting in additional methyl groups that may give rise to different properties of the polyketides. Here we present the results of a first 'proof of concept' study where a novel zearalenone analogue 5 was prepared that comprises an additional methyl group at C5'. Key steps in the synthesis of 5 include a Marshall-Tamaru reaction, a Suzuki cross-coupling reaction, and a Mitsunobu lactonization. Compared to the parent zearalenone (1), analogue 5 showed reduced binding to a panel of human protein kinases and no binding to human Hsp90. On the other hand, however, 5 turned out to be a potent (IC(50)=210 nM) inhibitor of human carbonyl reductase 1 (CBR1).

Original publication

DOI

10.1016/j.bmc.2008.11.076

Type

Journal article

Journal

Bioorganic & medicinal chemistry

Publication Date

01/2009

Volume

17

Pages

530 - 536

Addresses

Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.

Keywords

Humans, Acetates, Propionates, Macrolides, Zearalenone, Alcohol Oxidoreductases, Protein Kinases, Estrogens, Non-Steroidal, Protein Binding, Structure-Activity Relationship, HSP90 Heat-Shock Proteins