title: tert-Butylcarbamate-containing histone deacetylase inhibitors: apoptosis induction, cytodifferentiation, and antiproliferative activities in cancer cells.
abstract: Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2'-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Daniela
authors.initials: D
authors.lastname: Trisciuoglio
authors.forename: Maria
authors.initials: M
authors.lastname: Tardugno
authors.forename: Rosaria
authors.initials: R
authors.lastname: Benedetti
authors.forename: Donatella
authors.initials: D
authors.lastname: Labella
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.forename: Stefano
authors.initials: S
authors.lastname: Tomassi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D019073:HT29 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D056572:Histone Deacetylase Inhibitors; D011994:Recombinant Proteins; D012097:Repressor Proteins; C110550:HDAC1 protein, human; C400300:HDAC4 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases