The terminal substituents of 7伪, 6-hexanyl derivatives of estradiol determine their selective estrogen receptor modulator versus agonist activities

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• 作者：Kristi L. Hoffman^a ; ^b ; Estrella A. Foster^b ; Carolyn L. Smith^a ; ^b ; ^c ; ^{carolyns@bcm.edu}
• 关键词：4HT ; 4-hydroxytamoxifen ; AF-1 ; activation function-1 ; AF-2 ; activation function-2 ; C13 ; 7伪-(6-hydroxyhexanyl)-17尾-estradiol ; C14 ; 7伪-(6-benzyloxyhexanyl)-17尾-estradiol ; CBP ; cAMP response element-binding protein&ndash ; binding protein ; DME ; Dulbecco&rs
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：April, 2012
• 卷：77
• 期：5
• 页码：496-503
• 文件大小：462 K

摘要

Pure antiestrogens were clinically developed as alternative therapies for estrogen receptor (ER) positive breast cancers. Unlike the selective estrogen receptor modulators (SERMs), these antiestrogens are devoid of tissue-specific ER agonist activity. Many of these compounds are steroidal in nature, containing an estradiol (E2) structural core with long alkyl side chains at the C-7伪 position. Two novel 7伪-substituted E2 derivatives were evaluated that retain high binding affinity for ER. Compared to known pure antiestrogens, these compounds, referred to as compound 13 (C13) and C14, contain shorter 7伪 alkyl side chains and differ only in their terminal substituent: a hydroxyl moiety versus a benzyloxy group, respectively. Herein we assessed the effects of these compounds on ER transcriptional activity and report that despite their similar overall structure, C13 and C14 produce distinct cell type-specific responses. Of note, C13 functions as a mixed agonist/antagonist in Hela cells, inducing only weak ER transcriptional activity while preventing coactivator recruitment and stabilizing ER expression. However, this compound effectively stimulates ER activity in MCF-7 cells, does not increase ER levels and promotes cell proliferation on par with E2. Conversely, C14 stimulates transcriptional activity in both cell types and enhances ER-coactivator interactions. The activities of both compounds were inhibited by the pure antiestrogen ICI 182,780. Taken together, these results reveal that C13 is a SERM while C14 is an ER agonist, and indicate that the terminal modification of the C-7伪 hexanyl side chain of these estradiol derivatives is an important determinant of the biocharacter of these ER ligands.