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.

Rodrigo Mendoza-Sanchez ¹, David Cotnoir-White ², Justyna Kulpa ², Isabel Jutras ², Joshua Pottel ¹, Nicolas Moitessier ¹, Sylvie Mader ³, James L Gleason ⁴

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.

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