title: Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor.
abstract: The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Bowers
authors.forename: Nathan
authors.initials: N
authors.lastname: West
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Robert M
authors.initials: RM
authors.lastname: Williams
mesh_terms: 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*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013438:Sulfhydryl Compounds; D013844:Thiazoles; C527895:largazole; D000077337:Vorinostat; C087123:romidepsin