Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors
A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MC...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-01, Vol.59 (1), p.157-170 |
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| creator | Lv, Wei Liu, Jinzhong Skaar, Todd C O’Neill, Elizaveta Yu, Ge Flockhart, David A Cushman, Mark |
| description | A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment. |
| doi_str_mv | 10.1021/acs.jmedchem.5b01677 |
| format | Article |
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The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.5b01677</identifier><identifier>PMID: 26704594</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Aromatase Inhibitors - chemical synthesis ; Aromatase Inhibitors - pharmacology ; Catalytic Domain - drug effects ; Cell Line, Tumor ; DNA, Complementary - biosynthesis ; DNA, Complementary - drug effects ; Estrogen Receptor alpha - drug effects ; Estrogen Receptor beta - drug effects ; Female ; Humans ; Microsomes - drug effects ; Microsomes - enzymology ; Models, Molecular ; Molecular Docking Simulation ; Phenols - chemical synthesis ; Phenols - pharmacology ; Recombinant Proteins - chemical synthesis ; Recombinant Proteins - pharmacology ; RNA, Neoplasm - biosynthesis ; RNA, Neoplasm - drug effects ; Selective Estrogen Receptor Modulators - chemical synthesis ; Selective Estrogen Receptor Modulators - pharmacology ; Stereoisomerism ; Stilbenes - chemical synthesis ; Stilbenes - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2016-01, Vol.59 (1), p.157-170</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-2d48b179e8f218a7e9757ee1a8372fb6a0e6f26d70e213745dc0ad50bc466ea43</citedby><cites>FETCH-LOGICAL-a449t-2d48b179e8f218a7e9757ee1a8372fb6a0e6f26d70e213745dc0ad50bc466ea43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01677$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01677$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,315,781,785,886,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26704594$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lv, Wei</creatorcontrib><creatorcontrib>Liu, Jinzhong</creatorcontrib><creatorcontrib>Skaar, Todd C</creatorcontrib><creatorcontrib>O’Neill, Elizaveta</creatorcontrib><creatorcontrib>Yu, Ge</creatorcontrib><creatorcontrib>Flockhart, David A</creatorcontrib><creatorcontrib>Cushman, Mark</creatorcontrib><title>Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Aromatase Inhibitors - chemical synthesis</subject><subject>Aromatase Inhibitors - pharmacology</subject><subject>Catalytic Domain - drug effects</subject><subject>Cell Line, Tumor</subject><subject>DNA, Complementary - biosynthesis</subject><subject>DNA, Complementary - drug effects</subject><subject>Estrogen Receptor alpha - drug effects</subject><subject>Estrogen Receptor beta - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>Microsomes - drug effects</subject><subject>Microsomes - enzymology</subject><subject>Models, Molecular</subject><subject>Molecular Docking Simulation</subject><subject>Phenols - chemical synthesis</subject><subject>Phenols - pharmacology</subject><subject>Recombinant Proteins - chemical synthesis</subject><subject>Recombinant Proteins - pharmacology</subject><subject>RNA, Neoplasm - biosynthesis</subject><subject>RNA, Neoplasm - drug effects</subject><subject>Selective Estrogen Receptor Modulators - chemical synthesis</subject><subject>Selective Estrogen Receptor Modulators - pharmacology</subject><subject>Stereoisomerism</subject><subject>Stilbenes - chemical synthesis</subject><subject>Stilbenes - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV9v0zAUxS0EYqXwDRDyIy8p139ipy9IZRpj0tCkUZ4tJ7lpPCV2sR2kfnvStZvghRdfyfd3jq1zCHnPYMWAs0-2SauHEdumx3FV1sCU1i_IgpUcClmBfEkWAJwXXHFxQd6k9AAAgnHxmlxwpUGWa7kgux8Hn3tMLtHQ0W10-x79YcDcz4dH-sWl400YErWJbmIYbbYJ6Y3vXe1yiIlue5vpZkiBfg_tNNiM9CrlGHbo6T02uD9Sb8mrzg4J353nkvz8erW9_Fbc3l3fXG5uCyvlOhe8lVXN9BqrjrPKalzrUiMyWwnNu1pZQNVx1WpAzoSWZduAbUuoG6kUWimW5PPJdz_Vx3DQ52gHs49utPFggnXm3413vdmF36ZkcyhCzAYfzwYx_JowZTO61OAwWI9hSoZpBZUSMMNLIk9oE0NKEbvnZxiYY0dm7sg8dWTOHc2yD39_8Vn0VMoMwAl4lIcp-jmx_3v-AVMvpDI</recordid><startdate>20160114</startdate><enddate>20160114</enddate><creator>Lv, Wei</creator><creator>Liu, Jinzhong</creator><creator>Skaar, Todd C</creator><creator>O’Neill, Elizaveta</creator><creator>Yu, Ge</creator><creator>Flockhart, David A</creator><creator>Cushman, Mark</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160114</creationdate><title>Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors</title><author>Lv, Wei ; Liu, Jinzhong ; Skaar, Todd C ; O’Neill, Elizaveta ; Yu, Ge ; Flockhart, David A ; Cushman, Mark</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-2d48b179e8f218a7e9757ee1a8372fb6a0e6f26d70e213745dc0ad50bc466ea43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Aromatase Inhibitors - chemical synthesis</topic><topic>Aromatase Inhibitors - pharmacology</topic><topic>Catalytic Domain - drug effects</topic><topic>Cell Line, Tumor</topic><topic>DNA, Complementary - biosynthesis</topic><topic>DNA, Complementary - drug effects</topic><topic>Estrogen Receptor alpha - drug effects</topic><topic>Estrogen Receptor beta - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>Microsomes - drug effects</topic><topic>Microsomes - enzymology</topic><topic>Models, Molecular</topic><topic>Molecular Docking Simulation</topic><topic>Phenols - chemical synthesis</topic><topic>Phenols - pharmacology</topic><topic>Recombinant Proteins - chemical synthesis</topic><topic>Recombinant Proteins - pharmacology</topic><topic>RNA, Neoplasm - biosynthesis</topic><topic>RNA, Neoplasm - drug effects</topic><topic>Selective Estrogen Receptor Modulators - chemical synthesis</topic><topic>Selective Estrogen Receptor Modulators - pharmacology</topic><topic>Stereoisomerism</topic><topic>Stilbenes - chemical synthesis</topic><topic>Stilbenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lv, Wei</creatorcontrib><creatorcontrib>Liu, Jinzhong</creatorcontrib><creatorcontrib>Skaar, Todd C</creatorcontrib><creatorcontrib>O’Neill, Elizaveta</creatorcontrib><creatorcontrib>Yu, Ge</creatorcontrib><creatorcontrib>Flockhart, David A</creatorcontrib><creatorcontrib>Cushman, Mark</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lv, Wei</au><au>Liu, Jinzhong</au><au>Skaar, Todd C</au><au>O’Neill, Elizaveta</au><au>Yu, Ge</au><au>Flockhart, David A</au><au>Cushman, Mark</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-01-14</date><risdate>2016</risdate><volume>59</volume><issue>1</issue><spage>157</spage><epage>170</epage><pages>157-170</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26704594</pmid><doi>10.1021/acs.jmedchem.5b01677</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Aromatase Inhibitors - chemical synthesis Aromatase Inhibitors - pharmacology Catalytic Domain - drug effects Cell Line, Tumor DNA, Complementary - biosynthesis DNA, Complementary - drug effects Estrogen Receptor alpha - drug effects Estrogen Receptor beta - drug effects Female Humans Microsomes - drug effects Microsomes - enzymology Models, Molecular Molecular Docking Simulation Phenols - chemical synthesis Phenols - pharmacology Recombinant Proteins - chemical synthesis Recombinant Proteins - pharmacology RNA, Neoplasm - biosynthesis RNA, Neoplasm - drug effects Selective Estrogen Receptor Modulators - chemical synthesis Selective Estrogen Receptor Modulators - pharmacology Stereoisomerism Stilbenes - chemical synthesis Stilbenes - pharmacology |
| title | Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors |
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