Synthesis of 7α-substituted derivatives of 17β-estradiol

Jiang, Xiang‐Rong; Sowell, J. Walter; Zhu, Bao Ting

doi:10.1016/j.steroids.2005.11.008

Cited by 21 publications

(21 citation statements)

References 26 publications

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“…Due to the presence of the unnatural fl uorinated side chain, the synthesis of fulvestrant and analog compounds involves several steps from common steroids (Seimbille et al, 2002;Jiang et al, 2006). Treatment of 6,7-didehydro-19-nortestosterone acetate with Grignard reagent 2 in the presence of CuI introduces the C 9 side chain in the correct regio-and stereochemistry (Scheme 5.3).…”

Section: Fulvestrant/faslodexmentioning

confidence: 99%

Natural product chemistry and anticancer drug discovery

Huryn¹,

Wipf²

2008

Cancer Drug Design and Discovery

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Section: Fulvestrant/faslodexmentioning

confidence: 99%

Natural product chemistry and anticancer drug discovery

Huryn¹,

Wipf²

2008

Cancer Drug Design and Discovery

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“…ICI 182,780 was obtained from Tocris. C13 and C14 were generated as previously described and were the kind gift of Dr. Bao Ting Zhu [19]. …”

Section: Methodsmentioning

confidence: 99%

“…More recently [19], two novel E2 derivatives with extended C-7α side chains, 7α-(6-hydroxyhexanyl)-17β-estradiol (compound 13; C13) and 7α-(6-benzyloxyhexanyl)-17β-estradiol (compound 14; C14), that differ only in the terminal side chain substituent were generated (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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

2012

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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-7α position. Two novel 7α-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 7α 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-7α hexanyl side chain of these estradiol derivatives is an important determinant of the biocharacter of these ER ligands.

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“…Recently, we have compared a number of methods for the chemical synthesis of C-7α substituted E 2 derivatives [12]. Based on the improvements we recently made, we report here a simplified route for the chemical synthesis of a new C-7α biotinylated E 2 derivative (structure shown in Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Chemical synthesis and biochemical characterization of a biotinylated derivative of 17β-estradiol with a long side chain covalently attached to its C-7α position

Jiang

Wang

et al. 2008

Steroids

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High-affinity biotinylated derivatives of 17beta-estradiol (E2) are of value for isolation of various estrogen-binding proteins (including estrogen receptors) and also for studying protein-protein interactions involving these proteins. In this study, we developed a simplified route for the chemical synthesis of a biotinylated derivative of E2 (compound 7) with a side chain attached to its C-7alpha position. Compound 7, i.e., 7alpha-{7-[8-(biotinamido)-octanamido]-heptyl}-estradiol, could be readily synthesized from 6-keto-estradiol-3,17beta-di-tetrahydropyranyl ether (compound 2, which can be prepared from E2), with a final yield of 36%. In vitro receptor-binding assay confirmed that the synthesized affinity ligand has a high binding affinity for both human estrogen receptor alpha and beta. When the affinity ligand (compound 7) was immobilized with avidin on an affinity column, it effectively bound human estrogen receptor alpha, and the receptor protein could be selectively eluted with a biotin-containing buffer. Using the same affinity ligand, prolyl 4-hydroxylase beta-subunit (also known as protein disulfide isomerase) was identified as one of the high-affinity E2-binding proteins in the whole cytosolic protein mixture prepared from MCF-7 human breast cancer cells. Computational molecular modeling analysis showed that compound 7 can bind to human estrogen receptor alpha in a similar manner as ICI-182,780 and raloxifene, and their binding energy values are also similar.

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Synthesis of 7α-substituted derivatives of 17β-estradiol

Cited by 21 publications

References 26 publications

Natural product chemistry and anticancer drug discovery

Natural product chemistry and anticancer drug discovery

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

Chemical synthesis and biochemical characterization of a biotinylated derivative of 17β-estradiol with a long side chain covalently attached to its C-7α position

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