Extending Cross Metathesis To Identify Selective HDAC Inhibitors: Synthesis, Biological Activities, and Modeling

  • ACS Med Chem Lett. 2019 May 9;10(6):863-868. doi: 10.1021/acsmedchemlett.8b00440.
Samuel Bouchet  1 ,  Camille Linot  2 ,  Dusan Ruzic  3 ,  Danica Agbaba  3 ,  Benoit Fouchaq  4  5 ,  Joëlle Roche  5  6 ,  Katarina Nikolic  3 ,  Christophe Blanquart  2  5 ,  Philippe Bertrand  1  5
Affiliations
  • 1. Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 51106, B28, 86073 Poitiers cedex 09, France.
  • 2. CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.
  • 3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
  • 4. Eurofins-Cerep, Le Bois l'Evêque, 86600 Celle-L'Evescault, France.
  • 5. Réseau Epigénétique du Cancéropôle Grand Ouest, France.
  • 6. Laboratoire EBI, University of Poitiers, UMR CNRS 7267, F-86073 Poitiers, France.
PMID: 31223439 DOI: 10.1021/acsmedchemlett.8b00440
Abstract

Dissymmetric cross metathesis of alkenes as a convergent and general synthetic strategy allowed for the preparation of a new small series of human histone deacetylases (HDAC) inhibitors. Alkenes bearing Boc-protected hydroxamic acid and benzamide and trityl-protected thiols were used to provide the zinc binding groups and were reacted with alkenes bearing aromatic cap groups. One compound was identified as a selective HDAC6 Inhibitor lead. Additional biological evaluation in Cancer cell lines demonstrated its ability to stimulate the expression of the epithelial marker E-cadherin and tumor suppressor genes like SEMA3F and p21, suggesting a potential use of this compound for lung Cancer treatment. Molecular docking on all 11 HDAC isoforms was used to rationalize the observed biological results.