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 DiMaro, Ettore Novellino, Lucia Altucci, Donatella DelBufalo, Antonello Mai, Sandro Cosconati

Research output: Contribution to journalArticle

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 8b and 10c 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 8b and 10c elicited 18.4 and 21.4% apoptosis, respectively (SAHA: 16.9%), and the pyrrole anilide 9c displayed the highest cytodifferentiating effect (90.9%). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10c 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, 10c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60%.

Original languageEnglish
Pages (from-to)800-811
Number of pages12
JournalChemMedChem
Volume8
Issue number5
DOIs
Publication statusPublished - May 2013

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Keywords

  • Anilides
  • Apoptosis
  • Hydroxamates
  • Pyrroles
  • tert-butylcarbamates

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Valente, S., Trisciuoglio, D., Tardugno, M., Benedetti, R., Labella, D., Secci, D., Mercurio, C., Boggio, R., Tomassi, S., DiMaro, S., Novellino, E., Altucci, L., DelBufalo, D., Mai, A., & Cosconati, S. (2013). tert-Butylcarbamate-Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells. ChemMedChem, 8(5), 800-811. https://doi.org/10.1002/cmdc.201300005