title: Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: synthesis and biological evaluation.
abstract: The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn(2+) were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
authors.affiliation: Department of Medicinal and Biological Chemistry, The University of Toledo, OH 43606, USA.
authors.forename: Pravin
authors.initials: P
authors.lastname: Bhansali
authors.forename: Christin L
authors.initials: CL
authors.lastname: Hanigan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: L M Viranga
authors.initials: LM
authors.lastname: Tillekeratne
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D013844:Thiazoles; C527895:largazole; D006655:Histone Deacetylases; D015032:Zinc