Synthesis and\nEvaluation of 9-<i>epi</i>-Koshidacin B as Selective Inhibitor\nof Histone Deacetylase 1

A concise synthetic route to an epimer of the recently\nisolated\nbiologically active cyclic tetrapeptide koshidacin B has been developed,\nwhich featured a late-stage functionalization of a macrocyclic scaffold\nthrough a cross metathesis reaction. The synthetic 9-<i>epi</i>-koshidacin B showed marginal differences in spectroscopic behavior\nwith that of the natural product but exhibited conformational preferences\nsimilar to those reported for analogous substrate chlamydocin. Moreover,\nit exhibited a useful level of selective inhibition of biologically\nrelevant enzyme histone deacetylase 1 with an IC<sub>50</sub> value\nof 0.145 μM over two other isoforms. Docking studies indicate\nthat the natural product as well as its 9-epimer binds very similarly\nto the active site of HDAC1 indicating little influence of the configuration\nof the C9-stereocenter.