title: epigenetic multiple ligands: mixed histone/protein methyltransferase, acetyltransferase, and class III deacetylase (sirtuin) inhibitors.
abstract: A number of new compounds bearing two ortho-bromo- and ortho, ortho-dibromophenol moieties linked through a saturated/unsaturated, linear/(poly)cyclic spacer (compounds 1- 9) were prepared as simplified analogues of AMI-5 (eosin), a recently reported inhibitor of both protein arginine and histone lysine methyltransferases (PRMTs and HKMTs). Such compounds were tested against a panel of PRMTs (RmtA, PRMT1, and CARM1) and against human SET7 (a HKMT), using histone and nonhistone proteins as a substrate. They were also screened against HAT and SIRTs, because they are structurally related to some HAT and/or SIRT modulators. From the inhibitory data, some of tested compounds ( 1b, 1c, 4b, 4f, 4j, 4l, 7b, and 7f) were able to inhibit PRMTs, HKMT, HAT, and SIRTs with similar potency, thus behaving as multiple ligands for these epigenetic targets (epi-MLs). When tested on the human leukemia U937 cell line, the epi-MLs induced high apoptosis levels [i.e., 40.7% ( 4l) and 42.6% ( 7b)] and/or massive, dose-dependent cytodifferentiation [i.e., 95.2% ( 1c) and 96.1% ( 4j)], whereas the single-target inhibitors eosin, curcumin, and sirtinol were ineffective or showed a weak effect.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, Piazzale A. Moro 5, 00185 Rome, Italy. antonello.mai@uniroma1.it
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Donghang
authors.initials: D
authors.lastname: Cheng
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Andrea
authors.initials: A
authors.lastname: Perrone
authors.forename: Gerald
authors.initials: G
authors.lastname: Brosch
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Floriana
authors.initials: F
authors.lastname: De Bellis
authors.forename: Marco
authors.initials: M
authors.lastname: Miceli
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D004801:Eosine Yellowish-(YS) / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D037761:Sirtuins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099186:Histone Deacetylase 3
chemical_list: D000123:Acetyltransferases; D004801:Eosine Yellowish-(YS); D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D008024:Ligands; D008780:Methyltransferases; D037761:Sirtuins; D000099186:Histone Deacetylase 3