| Abstract
| - Azumamide E, a cyclotetrapeptide isolated from the sponge Mycale izuensis, is the most powerfulcarboxylic acid containing natural histone deacetylase (HDAC) inhibitor known to date. In this paper, wedescribe design and synthesis of two stereochemical variants of the natural product. These compoundshave allowed us to clarify the influence of side chain topology on the HDAC-inhibitory activity. The presentcontribution also reveals the identity of the recognition pattern between azumamides and the histonedeacetylase-like protein (HDLP) model receptor and reports the azumamide E unprecedented isoformselectivity on histone deacetylases class subtypes. From the present studies, a plausible model for theinteraction of azumamides with the receptor binding pocket is derived, providing a framework for the rationaldesign of new cyclotetrapeptide-based HDAC inhibitors as antitumor agents.
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