2. Academic Validation
  3. Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors

Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors

  • Eur J Med Chem. 2016 Jan 27:108:53-67. doi: 10.1016/j.ejmech.2015.11.010.
Florian Thaler 1,  Loris Moretti 2,  Raffaella Amici 3,  Agnese Abate 4,  Andrea Colombo 5,  Giacomo Carenzi 4,  Maria Carmela Fulco 4,  Roberto Boggio 6,  Giulio Dondio 5,  Stefania Gagliardi 5,  Saverio Minucci 7,  Luca Sartori 4,  Mario Varasi 4,  Ciro Mercurio 8
Affiliations

Affiliations

  • 1 Genextra Group, Congenia Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy. Electronic address: florian.thaler@ieo.eu.
  • 2 Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
  • 3 Genextra Group, Congenia Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
  • 4 Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
  • 5 NiKem Research Srl, Via Zambeletti 25, 20021 Baranzate, MI, Italy.
  • 6 Genextra Group, Congenia Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy.
  • 7 European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy; University of Milan, University of Milan, Via Celoria 26, 20133 Milan, Italy.
  • 8 Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy. Electronic address: ciro.mercurio@ieo.eu.
PMID: 26629860 DOI: 10.1016/j.ejmech.2015.11.010
Abstract

In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase Enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.

Keywords

Antiproliferation; Epigenetics; Histone deacetylases; Molecular modeling; Privileged structures.

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