title: Epigenetic profiling of the antitumor natural product psammaplin A and its analogues.
abstract: A collection of analogues of the dimeric natural product psammaplin A that differ in the substitution on the (halo)tyrosine aryl ring, the oxime and the diamine connection has been synthesized. The effects on cell cycle, induction of differentiation and apoptosis of the natural-product inspired series were measured on the human leukaemia U937 cell line. Epigenetic profiling included induction of p21(WAF1), effects on global H3 histone and tubulin acetylation levels as well as in vitro enzymatic assays using HDAC1, DNMT1, DNMT3A, SIRT1 and a peptide domain with p300/CBP HAT activity. Whereas the derivatives of psammaplin A with modifications in the length of the connecting chain, the oxime bond and the disulfide unit showed lower potency, the analogues with changes on the bromotyrosine ring exhibited activities comparable to those of the parent compound in the inhibition of HDAC1 and in the induction of apoptosis. The lack of HDAC1 activity of analogues modified on the disulfide bond suggests that its cleavage must occur in cells to produce the monomeric Zn(2+)-chelating thiol. This assumption is consistent with the molecular modelling of the complex of psammaplin A thiol with h-HDAC8. Only a weak inhibition of DNMT1, DNMT3A and residual activities with SIRT1 and a p300/CBP HAT peptide were measured for these compounds.
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain.
authors.forename: José
authors.initials: J
authors.lastname: García
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Franci
authors.forename: Raquel
authors.initials: R
authors.lastname: Pereira
authors.forename: Rosaria
authors.initials: R
authors.lastname: Benedetti
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Fátima
authors.initials: F
authors.lastname: Rodríguez-Barrios
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D057890:Epigenomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D040081:Protein Array Analysis; D014404:Tubulin / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004220:Disulfides; D006657:Histones; D008024:Ligands; D014404:Tubulin; C475724:bromotyrosine; C098378:psammaplin A; D014443:Tyrosine