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Synthesis and biological evaluation of cruentaren A analogues.

Authors
  • Vintonyak, Viktor V
  • Calà, Marcellino
  • Lay, Frank
  • Kunze, Brigitte
  • Sasse, Florenz
  • Maier, Martin E
Type
Published Article
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
Publication Date
Jan 01, 2008
Volume
14
Issue
12
Pages
3709–3720
Identifiers
DOI: 10.1002/chem.200701673
PMID: 18306263
Source
Medline
License
Unknown

Abstract

The complex macrolide cruentaren A is a highly selective and potent inhibitor of F-ATPase (F-type adenosine triphosphatase). As it shows some resemblance to benzolactone enamides like apicularen A, it was of interest to perform some structure-activity studies to delineate the key functional groups that are responsible for the activity. Building upon our previously developed route to cruentaren A, which is based on a ring-closing alkyne metathesis reaction (RCAM), several cruentaren analogues were prepared. Replacement of the 3-hydroxy hexanoic part with acids that lack the hydroxy group function resulted in a significant drop in cytotoxicity and F-ATPase inhibition. Furthermore, two enamide analogues 23 and 50 were synthesized. However, these compounds were only cytotoxic in the micromolar range. Under the conditions for cleavage of the C3 aromatic methyl ether, the enamide function was transformed to the corresponding oxazinanone, resulting in analogues 25 and 52.

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