Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids

Rodrigo Mendoza-Sanchez; David Cotnoir-White; Justyna Kulpa; Isabel Jutras; Joshua Pottel; Nicolas Moitessier; Sylvie Mader; James L Gleason

doi:10.1016/j.bmc.2015.11.005

Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids

Bioorg Med Chem. 2015 Dec 15;23(24):7597-606. doi: 10.1016/j.bmc.2015.11.005. Epub 2015 Nov 10.

Authors

Rodrigo Mendoza-Sanchez¹, David Cotnoir-White², Justyna Kulpa², Isabel Jutras², Joshua Pottel¹, Nicolas Moitessier¹, Sylvie Mader³, James L Gleason⁴

Affiliations

¹ Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada.
² Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
³ Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada. Electronic address: sylvie.mader@umontreal.ca.
⁴ Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada. Electronic address: jim.gleason@mcgill.ca.

PMID: 26613635
DOI: 10.1016/j.bmc.2015.11.005

Abstract

The combination of antiestrogens and histone deacetylase inhibitors (HDACi) has been found to be antiproliferative in breast cancer models. We designed and synthesized hybrid structures which combined structural features of the pure antiestrogen ICI-164,384 and HDACi's SAHA and entinostat in a single bifunctional molecule. The hybrids retained antiestrogenic and HDACi activity and, in the case of benzamide hybrids, were selective for Class I HDAC3 over Class II HDAC6. The hybrids possessed low micromolar to high nanomolar activity against both ER+ MCF-7 and ER- MDA-MB-231 breast cancer cell models.

Keywords: Antiestrogens; Breast cancer; Estrogen receptor; HDACi.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology
Breast / drug effects
Breast / metabolism
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Cell Line, Tumor
Estradiol / analogs & derivatives
Estradiol / chemical synthesis
Estradiol / chemistry
Estradiol / pharmacology
Estrogen Receptor Modulators / chemical synthesis
Estrogen Receptor Modulators / chemistry*
Estrogen Receptor Modulators / pharmacology*
Female
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
Molecular Docking Simulation
Polyunsaturated Alkamides / chemical synthesis
Polyunsaturated Alkamides / chemistry
Polyunsaturated Alkamides / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology

Substances

Antineoplastic Agents
Benzamides
Estrogen Receptor Modulators
Histone Deacetylase Inhibitors
Polyunsaturated Alkamides
Pyridines
entinostat
Estradiol
ICI 164384
Histone Deacetylases
histone deacetylase 3

Grants and funding

Canadian Institutes of Health Research/Canada