Cross metathesis with hydroxamate and benzamide BOC-protected alkenes to access HDAC inhibitors and their biological evaluation highlighted intrinsic activity of BOC-protected dihydroxamates

Vincent Zwick; Alessandra Nurisso; Claudia Simões-Pires; Samuel Bouchet; Nadine Martinet; Attila Lehotzky; Judit Ovadi; Muriel Cuendet; Christophe Blanquart; Philippe Bertrand

doi:10.1016/j.bmcl.2015.11.011

Cross metathesis with hydroxamate and benzamide BOC-protected alkenes to access HDAC inhibitors and their biological evaluation highlighted intrinsic activity of BOC-protected dihydroxamates

Bioorg Med Chem Lett. 2016 Jan 1;26(1):154-9. doi: 10.1016/j.bmcl.2015.11.011. Epub 2015 Nov 11.

Affiliations

¹ School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest-Ansermet, 1211 Geneva, Switzerland.
² Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 521106, B28, 86073 Poitiers, France; Réseau Epigénétique du Cancéropôle Grand Ouest, France.
³ Institut de chimie, UMR CNRS 7272, UNSA, F-06108 Nice, France.
⁴ Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, 1117 Budapest Hungary.
⁵ Inserm, UMR 892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France; Réseau Epigénétique du Cancéropôle Grand Ouest, France.
⁶ Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 521106, B28, 86073 Poitiers, France; Réseau Epigénétique du Cancéropôle Grand Ouest, France. Electronic address: philippe.bertrand@univ-poitiers.fr.

PMID: 26611919
DOI: 10.1016/j.bmcl.2015.11.011

Abstract

Conditions for the metathesis of alkenes in the convergent synthesis of HDAC inhibitors have been improved by continuous catalyst flow injection in the reaction media. Intermediate and target compounds obtained were tested for their ability to induce HDAC inhibition and tubulin acetylation, revealing the key role of the tert-butyloxycarbonyl (BOC) group for more HDAC6 selectivity. Molecular modelling added rationale for this BOC effect.

Keywords: Cancer; Histone deacetylases; Metathesis; Tubulin.

Publication types

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

MeSH terms

Alkenes / chemistry*
Benzamides / chemistry*
Dose-Response Relationship, Drug
Formic Acid Esters / chemistry*
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / chemistry*
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Alkenes
Benzamides
Formic Acid Esters
Histone Deacetylase Inhibitors
Hydroxamic Acids
t-butyloxycarbonyl group
benzamide
Histone Deacetylases