1027785-39-2Relevant academic research and scientific papers
Total synthesis of the bicyclic depsipeptide hdac inhibitors spiruchostatins a and b, 5″-epi-spiruchostatin b, fk228 (fr901228) and preliminary evaluation of their biological activity
Narita, Koichi,Kikuchi, Takuya,Watanabe, Kazuhiro,Takizawa, Toshiya,Oguchi, Takamasa,Kudo, Kyosuke,Matsuhara, Keisuke,Abe, Hideki,Yamori, Takao,Yoshida, Minoru,Katoh, Tadashi
supporting information; experimental part, p. 11174 - 11186 (2010/04/29)
The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5″-ep(-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps : i) a JuliaKocienski olefination of a 1,3-propanediol-derived sulfone and a L- or Dmalic acid-derived aldehyde to access the most synthetically challenging unit, (35 or 3R,4E)-3-hydroxy-7- mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D- cysteinecontaining segment with a D-alanineor D-valine-containing segment to directly assemble the corresponding secoacids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5″ stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5″-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC50 = 2.4 nM) over class II HDAC6 (IC 50 = 3900nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC50 values.
Total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, from a microorganism
Takizawa, Toshiya,Watanabe, Kazuhiro,Narita, Koichi,Oguchi, Takamasa,Abe, Hideki,Katoh, Tadashi
, p. 1677 - 1679 (2008/12/22)
The first total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, was achieved in a convergent manner; the synthesis established stereochemistry at the C5″ position. The Royal Society of Chemistry.
