Flexible estrogen receptor modulators: Design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells
Flexible estrogen receptor modulators: Design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells
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DOI：
10.1021/jm001119l
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发表时间：
2001-03-29
影响因子：
7.3
通讯作者：
Zisterer, DM
中科院分区：
文献类型：
--
作者：
Meegan, MJ;Hughes, RB;Zisterer, DM
尽管许多系列的雌激素受体拮抗剂继续被生产，但大多数是现有调节剂的直接结构类似物。为了研究雌激素受体对柔性配体的耐受性，制备了一系列新型柔性雌激素受体拮抗剂，并研究了它们对人MCF-7乳腺肿瘤细胞的抗增殖作用。这些化合物中的每一种都偏离了与常见的他莫昔芬类似物相关的传统的三苯基乙烯骨架，通过在芳基环之一和乙烯基团之间引入灵活的亚甲基（苄基）间隔基团，并通过在基本侧链部分的变化。当与他莫昔芬标准品一起测定时，所制备的化合物在针对MCF-7人乳腺癌细胞系的抗增殖测定中表现出高效力，具有低细胞毒性和高结合亲和力。进行计算研究以研究化合物与人雌激素受体a配体结合结构域（ER-LBD）内的特定残基的潜在相互作用，预测这些化合物以抗雌激素方式结合在ER-LBD内，并与先前在ER-LBD激动剂/拮抗剂共晶体结构中鉴定的那些重要残基相互作用。这些化合物进一步说明了雌激素受体在配体柔性耐受性方面的折衷性质。
Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds ' potential interactions with specific residues within the human estrogen receptor a ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.