title: Synthesis and biological properties of novel, uracil-containing histone deacetylase inhibitors.
abstract: A novel series of compounds containing a uracil moiety as the connection unit between a phenyl/phenylalkyl portion and a N-hydroxy-polymethylenealkanamide or -methylenecinnamylamide group (uracil-based hydroxamic acids, UBHAs) was tested against maize histone deacetylases (HDACs) and mouse HDAC1. Compounds with a phenyl/benzyl ring at the uracil-C6 position and bearing 4-5 carbon units as well as a m- or p-methylenecinnamyl moiety as a spacer were the most potent inhibitors. In cell-based human HDAC1 and HDAC4 assays, the two UBHAs tested inhibited the HDAC1 but not HDAC4 immunoprecipitate activity. When tested in human leukemia U937 cells, some UBHAs produced G1 phase arrest of the cell cycle. Moreover, 1j showed high antiproliferative and dose-dependent granulocytic differentiation properties. The tested UBHAs displayed weak p21WAF1/CIP1 induction in U937 cells, and 1d and 1j showed high histone H3 and alpha-tubulin acetylation effects.
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Silvia
authors.initials: S
authors.lastname: Simeoni
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Giorgia
authors.initials: G
authors.lastname: Botta
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Marco
authors.initials: M
authors.lastname: Miceli
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Gerald
authors.initials: G
authors.lastname: Brosch
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D020298:U937 Cells; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D003313:Zea mays / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D014404:Tubulin; D014498:Uracil; C110550:HDAC1 protein, human; C400300:HDAC4 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases