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

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• 作者：Rodrigo Mendoza-Sanchez^a ; David Cotnoir-White^b ; Justyna Kulpa^b ; Isabel Jutras^b ; Joshua Pottel^a ; Nicolas Moitessier^a ; Sylvie Mader^b ; ^{sylvie.mader@umontreal.ca" class="auth_mail" title="E-mail the corresponding author} ; James L. Gleason^a ; ^{jim.gleason@mcgill.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Estrogen receptor ; Antiestrogens ; HDACi ; Breast cancer
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：15 December 2015
• 年：2015
• 卷：23
• 期：24
• 页码：7597-7606
• 全文大小：1357 K

文摘

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.