抄録
Histone deacetylases (HDACs) regulate gene expression. Although more than ten human HDACs have been determined, exact roles of them are still unclear. To investigate each role of HDACs, selective inhibitors are important. Spiruchostatin A is a potent histone deacetylase inhibitior, which is a bicyclic depsipeptide consisting of Val-statine, D-cysteine, D-alanine, and β-hydroxy acid. Toward a combinatorial library synthesis of its analogues, we have achieved a total synthesis of spiruchostatin A in both solution-phase and solid-phase. The β-hydroxy acid was prepared by asymmetric aldol reaction of the Zr-enolate of acetate derivative utilizing Seebach chiral auxiliary. After sequential coupling of Val-statine, Fmoc-D-Cys(Trt)-OH, Fmoc-D-Ala-OH, and the β-hydroxy acid, macrolactonization was achieved by Shiina's method in excellent yield. Finally, oxidative deprotection and disulfide bond formation provided spiruchostatin A. A chemical probe prepared from spiruchostatin A was utilized for elucidation of natural product/protein network analysis by a nano-flow LC-MS/MS system. It was found that 20 interacting proteins including HDAC1 and HDAC2 were fished-out. The results exhibit this method can be utilized for elucidation of not only a target protein but also interacting proteins in high speed.
