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Incorporation of histone deacetylase inhibitory activity into the core of tamoxifen - A new hybrid design paradigm.

Palermo AF, Diennet M, El Ezzy M, Williams BM, Cotnoir-White D, Mader S, Gleason JL

Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada.

Hybrid antiestrogen/histone deacetylase (HDAC) inhibitors were designed by appending zinc binding groups to the 4-hydroxystilbene core of 4-hydroxytamoxifen. The resulting hybrids were fully bifunctional, and displayed high nanomolar to low micromolar IC50 values against both the estrogen receptor α (ERα) and HDACs in vitro and in cell-based assays. The hybrids were antiproliferative against ER+ MCF-7 breast cancer cells, with hybrid 28b possessing an improved activity profile compared to either 4-hydroxytamoxifen or SAHA. Hybrid 28b displayed gene expression patterns that reflected both ERα and HDAC inhibition.

Bioorg. Med. Chem. 2018;26(15):4428-4440.

Pubmed ID: 30078609

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