title: Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets.
abstract: Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC(50) 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.
authors.affiliation: Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Matthias G J
authors.initials: MG
authors.lastname: Baud
authors.forename: Thomas
authors.initials: T
authors.lastname: Leiser
authors.forename: Patricia
authors.initials: P
authors.lastname: Haus
authors.forename: Sharon
authors.initials: S
authors.lastname: Samlal
authors.forename: Ai Ching
authors.initials: AC
authors.lastname: Wong
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wood
authors.forename: Vanessa
authors.initials: V
authors.lastname: Petrucci
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Hughes
authors.forename: Lakjaya
authors.initials: L
authors.lastname: Buluwela
authors.forename: Fabrice
authors.initials: F
authors.lastname: Turlais
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Meyer-Almes
authors.forename: Andrew J P
authors.initials: AJ
authors.lastname: White
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fuchter
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019281:Dimerization; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007527:Isoenzymes; D011355:Prodrugs; D014404:Tubulin; C098378:psammaplin A; D014443:Tyrosine; D004248:DNA (Cytosine-5-)-Methyltransferases