Min Jian, Guillen Valeria Sanabria, Sharma Abhishek, Zhao Yuechao, Ziegler Yvonne, Gong Ping, Mayne Christopher G, Srinivasan Sathish, Kim Sung Hoon, Carlson Kathryn E, Nettles Kendall W, Katzenellenbogen Benita S, Katzenellenbogen John A
Department of Cancer Biology, The Scripps Research Institute , Jupiter, Florida 33458, United States.
J Med Chem. 2017 Jul 27;60(14):6321-6336. doi: 10.1021/acs.jmedchem.7b00585. Epub 2017 Jul 14.
To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and amide analogs. All compounds were high affinity estrogen receptor α (ERα) ligands but displayed a range of efficacies and potencies as antiproliferative and ERα-downregulating agents. There were large differences in activity between compounds having minor structural changes, but antiproliferative and ERα-downregulating efficacies generally paralleled one another. Some compounds with side chain polar groups had particularly high affinities. The secondary carboxamides had the best cellular activities, and the 3-hydroxypropylamide was as efficacious as fulvestrant in suppressing cell proliferation and gene expression. This study has produced structurally novel antiestrogens based on a simple adamantyl core structure with acrylate side chains optimized for cellular antagonist activity.
为了寻找在治疗乳腺癌方面更有效的新型抗雌激素药物，我们探索了许多抗雌激素药物中使用的丙烯酸侧链的替代物。为便于研究，我们使用了一个简单的金刚烷基配体核心，通过避免立体化学问题，能够快速合成丙烯酸酯酮、酯和酰胺类似物。所有化合物都是高亲和力雌激素受体α（ERα）配体，但作为抗增殖剂和ERα下调剂，它们表现出一系列的效力和效能。结构上有微小变化的化合物之间活性存在很大差异，但抗增殖和ERα下调效能通常相互平行。一些带有侧链极性基团的化合物具有特别高的亲和力。仲羧酰胺具有最佳的细胞活性，3-羟丙基酰胺在抑制细胞增殖和基因表达方面与氟维司群一样有效。本研究基于一个简单的金刚烷基核心结构，产生了结构新颖的抗雌激素药物，其丙烯酸酯侧链针对细胞拮抗剂活性进行了优化。
