title: Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities.
abstract: The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner. The method features the amide coupling of a D-leucine-D-cysteine- or D-valine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization. The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A-D in comparison with the clinically approved depsipeptide FK228 (romidepsin). Novel aspects of structure-activity relationships (SAR) were revealed.
authors: Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors: Koichi
authors: K
authors: Narita
authors: Yurie
authors: Y
authors: Fukui
authors: Yui
authors: Y
authors: Sano
authors: Takao
authors: T
authors: Yamori
authors: Akihiro
authors: A
authors: Ito
authors: Minoru
authors: M
authors: Yoshida
authors: Tadashi
authors: T
authors: Katoh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D004791:Enzyme Inhibitors; C568645:spiruchostatin C; C582774:spiruchostatin D; D006655:Histone Deacetylases