2. Academic Validation
  3. Biphenyl-4-yl-acrylohydroxamic acids: Identification of a novel indolyl-substituted HDAC inhibitor with antitumor activity

Biphenyl-4-yl-acrylohydroxamic acids: Identification of a novel indolyl-substituted HDAC inhibitor with antitumor activity

  • Eur J Med Chem. 2016 Apr 13:112:99-105. doi: 10.1016/j.ejmech.2016.02.001.
Raffaella Cincinelli 1,  Vincent Zwick 2,  Loana Musso 1,  Valentina Zuco 3,  Michelandrea De Cesare 3,  Franco Zunino 3,  Claudia Simoes-Pires 2,  Alessandra Nurisso 2,  Giuseppe Giannini 4,  Muriel Cuendet 2,  Sabrina Dallavalle 5
Affiliations

Affiliations

  • 1 Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy.
  • 2 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 11, Switzerland.
  • 3 Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milano, Italy.
  • 4 R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00071 Pomezia, Roma, Italy.
  • 5 Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy. Electronic address: sabrina.dallavalle@unimi.it.
PMID: 26890116 DOI: 10.1016/j.ejmech.2016.02.001
Abstract

Modification of the cap group of biphenylacrylohydroxamic acid-based HDAC inhibitors led to the identification of a new derivative (3) characterized by an indolyl-substituted 4-phenylcinnamic skeleton. Molecular docking was used to predict the optimal conformation in the class I HDACs active site. Compound 3 showed HDAC inhibitory activity and antiproliferative activity against a panel of tumor cell lines, in the low μM range. The compound was further tested in vitro for acetylation of histone H4 and Other non-histone proteins, and in vivo in a colon carcinoma model, showing significant proapoptotic and antitumor activities.

Keywords

Antiproliferative activity; Antitumor activity; HDAC inhibitors; Hydroxamic acids; Synthesis.

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