Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montreal, QC, H3A 0B8, Canada.
Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 Chemin de Polytechnique, Montréal, QC, H3T 1J4, Canada.
Eur J Med Chem. 2024 Aug 5;274:116533. doi: 10.1016/j.ejmech.2024.116533. Epub 2024 May 24.
Antiestrogen/histone deacetylase inhibitor (HDACi) hybrids were designed by merging structures of raloxifene with suberoylanilide hydroxamic acid, incorporating the HDACi unit into the phenolic ring of the antiestrogen. These hybrids were synthesized with a range of HDACi chain lengths and assessed for bifunctionality. Four hybrids, 21 (YW471), 22 (YW490), 27(YW486), and 28 (YW487) showed good potency both as antiestrogens in a BRET assay and in a fluorometric HDACi assay. The antiproliferative activity of the hybrids was demonstrated in both ER+ MCF7 and ER- MDA-MB-231 breast cancer cell lines.
设计了一种结合了雷洛昔芬结构和琥珀酰亚胺基羟肟酸的抗雌激素/组蛋白去乙酰化酶抑制剂（HDACi）杂合体，将 HDACi 单元整合到抗雌激素的酚环中。这些杂合体的 HDACi 链长范围不同，并对其双功能特性进行了评估。四种杂合体，即 21（YW471）、22（YW490）、27（YW486）和 28（YW487），在 BRET 测定和荧光 HDACi 测定中均表现出良好的作为抗雌激素的活性。这些杂合体在 ER+ MCF7 和 ER- MDA-MB-231 乳腺癌细胞系中的增殖活性也得到了证实。
