title: Total synthesis of burkholdacs A and B and 5,6,20-tri-epi-burkholdac A: HDAC inhibition and antiproliferative activity.
abstract: The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors burkholdacs A and B were efficiently synthesized in a highly convergent and unified manner. The synthesis features the amide coupling of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-methionine-containing segment to directly assemble the corresponding seco-acids, key precursors for macrolactonization. Using the same methodology, 5,6,20-tri-epi-burkholdac A was also synthesized. HDAC inhibitory assays and cell-growth inhibition analyses of the synthesized depsipeptides demonstrated the potency order of this class of bicyclic depsipeptides as compared to the clinically approved depsipeptide FK228 (romidepsin). Novel structure-activity relationships within this class of compounds were also revealed.
authors.affiliation: Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Fukui
authors.affiliation: Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Narita
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Singo
authors.initials: S
authors.lastname: Dan
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan; Pharmaceuticals and Medical Devices Agency (PMDA), 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.affiliation: Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: katoh@tohoku-pharm.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Katoh
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C558622:burkholdac A; C558623:burkholdac B
keywords: Bicyclic depsipeptide; Burkholdacs; Histone deacetylase inhibitors; Natural products; Total synthesis