Cyclopeptide FR235222 isolated from the fermn. broth of Acremonium sp. exhibited a potent inhibition of HDAC (mammalian histone deacetylase), has been synthesized. The first key intermediate for the synthesis of of cyclopeptide, (2S,9R)-2-amino-9-hydroxy-8-oxodecanoic acid (Ahoda), was prepd. from L-Glu via Wittig-Horner-Emmons reaction, and the second key intermediate, trans-4-methyl-D-proline (4-MePro), was prepd. via stereoselective methylation and lactamization. A 3D model for cyclopeptide inhibitor interaction with the HDAC active site highlights the differences between the binding mode of small-mol. and cyclopeptide inhibitors.
Total Synthesis, NMR Solution Structure, and Binding Model of the Potent Histone Deacetylase Inhibitor FR235222
RODRIQUEZ, Manuela;TERRACCIANO, Stefania;BRUNO, Ines;BIFULCO, Giuseppe;
2006
Abstract
Cyclopeptide FR235222 isolated from the fermn. broth of Acremonium sp. exhibited a potent inhibition of HDAC (mammalian histone deacetylase), has been synthesized. The first key intermediate for the synthesis of of cyclopeptide, (2S,9R)-2-amino-9-hydroxy-8-oxodecanoic acid (Ahoda), was prepd. from L-Glu via Wittig-Horner-Emmons reaction, and the second key intermediate, trans-4-methyl-D-proline (4-MePro), was prepd. via stereoselective methylation and lactamization. A 3D model for cyclopeptide inhibitor interaction with the HDAC active site highlights the differences between the binding mode of small-mol. and cyclopeptide inhibitors.File in questo prodotto:
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