Mendoza-Sanchez Rodrigo, Cotnoir-White David, Kulpa Justyna, Jutras Isabel, Pottel Joshua, Moitessier Nicolas, Mader Sylvie, Gleason James L
Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada.
Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
Bioorg Med Chem. 2015 Dec 15;23(24):7597-606. doi: 10.1016/j.bmc.2015.11.005. Epub 2015 Nov 10.
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.
在乳腺癌模型中，抗雌激素与组蛋白去乙酰化酶抑制剂（HDACi）的联合使用已被发现具有抗增殖作用。我们设计并合成了杂合结构，该结构在单个双功能分子中结合了纯抗雌激素ICI-164,384和HDACi的SAHA及恩替诺特的结构特征。这些杂合体保留了抗雌激素和HDACi活性，并且对于苯甲酰胺杂合体而言，相对于II类HDAC6，对I类HDAC3具有选择性。这些杂合体对雌激素受体阳性（ER+）的MCF-7和雌激素受体阴性（ER-）的MDA-MB-231乳腺癌细胞模型均具有低微摩尔到高纳摩尔的活性。
