title: Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability.
abstract: The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life ≤5 min) to the thiol which has a half-life of 51 min.
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Hanae
authors.initials: H
authors.lastname: Benelkebir
authors.forename: Sabrina
authors.initials: S
authors.lastname: Marie
authors.forename: Annette L
authors.initials: AL
authors.lastname: Hayden
authors.forename: Jason
authors.initials: J
authors.lastname: Lyle
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Crabb
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D013844:Thiazoles; C527895:largazole