Total Synthesis
and Full Histone Deacetylase Inhibitory
Profiling of Azumamides A–E as Well as β<sup>2</sup>- <i>epi</i>-Azumamide E and β<sup>3</sup>-<i>epi</i>-Azumamide E
- Publication date
- Publisher
Abstract
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 β-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