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