title: 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.
abstract: The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S 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-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; 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 (IC(50)=2.4 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.
authors.affiliation: Laboratory of Synthetic Medicinal Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Narita
authors.forename: Takuya
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Takizawa
authors.forename: Takamasa
authors.initials: T
authors.lastname: Oguchi
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kudo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsuhara
authors.forename: Hideki
authors.initials: H
authors.lastname: Abe
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tadashi
authors.initials: T
authors.lastname: Katoh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C529984:spiruchostatin B; C485419:spiruchostatin A; C087123:romidepsin; D006655:Histone Deacetylases