tert-Butylcarbamate-containing histone deacetylase inhibitors: apoptosis induction, cytodifferentiation, and antiproliferative activities in cancer cells

Sergio Valente; Daniela Trisciuoglio; Maria Tardugno; Rosaria Benedetti; Donatella Labella; Daniela Secci; Ciro Mercurio; Roberto Boggio; Stefano Tomassi; Salvatore Di Maro; Ettore Novellino; Lucia Altucci; Donatella Del Bufalo; Antonello Mai; Sandro Cosconati

doi:10.1002/cmdc.201300005

tert-Butylcarbamate-containing histone deacetylase inhibitors: apoptosis induction, cytodifferentiation, and antiproliferative activities in cancer cells

ChemMedChem. 2013 May;8(5):800-11. doi: 10.1002/cmdc.201300005. Epub 2013 Mar 25.

Authors

Sergio Valente¹, Daniela Trisciuoglio, Maria Tardugno, Rosaria Benedetti, Donatella Labella, Daniela Secci, Ciro Mercurio, Roberto Boggio, Stefano Tomassi, Salvatore Di Maro, Ettore Novellino, Lucia Altucci, Donatella Del Bufalo, Antonello Mai, Sandro Cosconati

Affiliation

¹ Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le A. Moro 5, 00185 Roma, Italy.

PMID: 23526814
DOI: 10.1002/cmdc.201300005

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 %.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Cell Differentiation / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HCT116 Cells
HT29 Cells
Histone Deacetylase 1 / antagonists & inhibitors
Histone Deacetylase 1 / metabolism
Histone Deacetylase 6
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
K562 Cells
MCF-7 Cells
Models, Molecular
Molecular Structure
Neoplasms / drug therapy
Neoplasms / pathology*
Recombinant Proteins / metabolism
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / metabolism
Structure-Activity Relationship
U937 Cells

Substances

Antineoplastic Agents
Carbamates
Histone Deacetylase Inhibitors
Recombinant Proteins
Repressor Proteins
HDAC1 protein, human
HDAC4 protein, human
HDAC6 protein, human
Histone Deacetylase 1
Histone Deacetylase 6
Histone Deacetylases