Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 2, Pages 530-536Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.11.076
Keywords
Macrolides; Zearalenone; Natural product analogues; Polyketides; Carbonyl reductase 1
Funding
- Deutsche Forschungsgemeinschaft [Ma 1012/23-1]
- Fonds der Chemischen Industrie
- Bayer Science and Education Foundation
- German National Academic Foundation (Studienstiftung des deutschen Volkes)
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck and Co., Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
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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 (IC50 = 210 nM) inhibitor of human carbonyl reductase 1 (CBR1). (C) 2008 Elsevier Ltd. All rights reserved.
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