Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 16, Pages 6512-6520Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4008449
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Funding
- Lundbeck Foundation
- Danish Independent Research Council-Natural Sciences [10-080907]
- Carlsberg Foundation
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Cyclic tetrapeptide and depsipeptide natural products have proven useful as biological probes and drug candidates due to their potent activities as histone deacetylase (HDAC) inhibitors. Here, we present the syntheses of a class of cyclic tetrapeptide HDAC inhibitors, the azumamides, by a concise route in which the key step in preparation of the noncanonical disubstituted beta-amino acid building block was an Ellman-type Mannich reaction. By tweaking the reaction conditions during this transformation, we gained access to the natural products as well as two epimeric homologues. Thus, the first total syntheses of azumamides B-D corroborated the originally assigned structures, and the synthetic efforts enabled the first full profiling of HDAC inhibitory properties of the entire selection of azumamides A-E. This revealed unexpected differences in the relative potencies within the class and showed that azumamides C and E are both potent inhibitors of HDAC10 and HDAC11.
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