Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator

Selective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11–2,1 [methyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate] and E11–2,2 [ethyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)ac...

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Veröffentlicht in:The journal of clinical endocrinology and metabolism 2004-07, Vol.89 (7), p.3527-3535
Hauptverfasser: Zhang, Jing-xin, Labaree, David C., Mor, Gil, Hochberg, Richard B.
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container_issue 7
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container_title The journal of clinical endocrinology and metabolism
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creator Zhang, Jing-xin
Labaree, David C.
Mor, Gil
Hochberg, Richard B.
description Selective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11–2,1 [methyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate] and E11–2,2 [ethyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11β with a carboxymethyl group. The shorter methyl ester, E11–2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11–2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER α or β. In the rat, E11–2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11–2,2 with its short, nonpolar side-chain, lacks this critical structure, presenting the possibility that it might act through a unique mechanism.
doi_str_mv 10.1210/jc.2003-032005
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We have synthesized two analogs, E11–2,1 [methyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate] and E11–2,2 [ethyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11β with a carboxymethyl group. The shorter methyl ester, E11–2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11–2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER α or β. In the rat, E11–2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11–2,2 with its short, nonpolar side-chain, lacks this critical structure, presenting the possibility that it might act through a unique mechanism.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Body Weight - drug effects</subject><subject>Bone and Bones - drug effects</subject><subject>Bone and Bones - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cholesterol - blood</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endocrinopathies</subject><subject>Estradiol - analogs &amp; derivatives</subject><subject>Estradiol - chemistry</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen Antagonists - chemistry</subject><subject>Estrogen Antagonists - pharmacology</subject><subject>Estrogen Receptor alpha</subject><subject>Estrogen Receptor beta</subject><subject>Estrogens - agonists</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Hydrocarbons</subject><subject>Medical sciences</subject><subject>Methane - analogs &amp; derivatives</subject><subject>Organ Size - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Estrogen - drug effects</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Selective Estrogen Receptor Modulators - chemistry</subject><subject>Selective Estrogen Receptor Modulators - pharmacology</subject><subject>Transfection</subject><subject>Uterus - drug effects</subject><subject>Uterus - pathology</subject><subject>Vertebrates: endocrinology</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1vEzEQhlcIREPhyhH5ArcN_lp791hVpSC1QmqpxM0avJPGwbGD7W3UC78dRxs-LhysmbGfecfzNs1rRpeMM_p-Y5ecUtFSUUP3pFmwQXatZoN-2iwo5awdNP960rzIeUMpk7ITz5sT1nFJleSL5udFLineYyAlkrNQHP6u966sCZBbF-49kmss60ePAcllitOO3GCefKlvxAUCgdyFKU_gyW3BFN14yNCjLe4ByZ8RN2hxV2Ii13GcPNTsZfNsBT7jq2M8be4-XHw5_9hefb78dH521VrZcd6yTg8aKKUWgFGueyks2EEBp_0IAhTTknUdWAEUpJQgpFLD2DMt6jWiOG3ezbq7FH9MdUezddmi9xAwTtkopXqtOl3B5QzaFHNOuDK75LaQHg2j5uC42VhzcNzMjteGN0fl6dsWx7_40eIKvD0CkC34VYJgXf6HG0RdjlZOztw--mpi_u6nPSazRvBlberuVCrdt3WopLpWbT36IN_NbRjGaJMLuEuYs9nEKYVq6f_-_QvlDaqB</recordid><startdate>200407</startdate><enddate>200407</enddate><creator>Zhang, Jing-xin</creator><creator>Labaree, David C.</creator><creator>Mor, Gil</creator><creator>Hochberg, Richard B.</creator><general>Endocrine Society</general><general>Copyright by The Endocrine Society</general><scope>IQODW</scope><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></search><sort><creationdate>200407</creationdate><title>Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator</title><author>Zhang, Jing-xin ; Labaree, David C. ; Mor, Gil ; Hochberg, Richard B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4522-15797a000caa1027843cac96a208da3a6174155ac3a0a444a34669d8173155ee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Body Weight - drug effects</topic><topic>Bone and Bones - drug effects</topic><topic>Bone and Bones - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cholesterol - blood</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endocrinopathies</topic><topic>Estradiol - analogs &amp; derivatives</topic><topic>Estradiol - chemistry</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen Antagonists - chemistry</topic><topic>Estrogen Antagonists - pharmacology</topic><topic>Estrogen Receptor alpha</topic><topic>Estrogen Receptor beta</topic><topic>Estrogens - agonists</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Hydrocarbons</topic><topic>Medical sciences</topic><topic>Methane - analogs &amp; derivatives</topic><topic>Organ Size - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Estrogen - drug effects</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Selective Estrogen Receptor Modulators - chemistry</topic><topic>Selective Estrogen Receptor Modulators - pharmacology</topic><topic>Transfection</topic><topic>Uterus - drug effects</topic><topic>Uterus - pathology</topic><topic>Vertebrates: endocrinology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Jing-xin</creatorcontrib><creatorcontrib>Labaree, David C.</creatorcontrib><creatorcontrib>Mor, Gil</creatorcontrib><creatorcontrib>Hochberg, Richard B.</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Jing-xin</au><au>Labaree, David C.</au><au>Mor, Gil</au><au>Hochberg, Richard B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2004-07</date><risdate>2004</risdate><volume>89</volume><issue>7</issue><spage>3527</spage><epage>3535</epage><pages>3527-3535</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><coden>JCEMAZ</coden><abstract>Selective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11–2,1 [methyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate] and E11–2,2 [ethyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11β with a carboxymethyl group. The shorter methyl ester, E11–2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11–2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER α or β. In the rat, E11–2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11–2,2 with its short, nonpolar side-chain, lacks this critical structure, presenting the possibility that it might act through a unique mechanism.</abstract><cop>Bethesda, MD</cop><pub>Endocrine Society</pub><pmid>15240642</pmid><doi>10.1210/jc.2003-032005</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
Biological and medical sciences
Body Weight - drug effects
Bone and Bones - drug effects
Bone and Bones - pathology
Cell Line, Tumor
Cholesterol - blood
Dose-Response Relationship, Drug
Endocrinopathies
Estradiol - analogs & derivatives
Estradiol - chemistry
Estradiol - pharmacology
Estrogen Antagonists - chemistry
Estrogen Antagonists - pharmacology
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogens - agonists
Female
Fundamental and applied biological sciences. Psychology
Humans
Hydrocarbons
Medical sciences
Methane - analogs & derivatives
Organ Size - drug effects
Rats
Rats, Sprague-Dawley
Receptors, Estrogen - drug effects
Receptors, Estrogen - metabolism
Selective Estrogen Receptor Modulators - chemistry
Selective Estrogen Receptor Modulators - pharmacology
Transfection
Uterus - drug effects
Uterus - pathology
Vertebrates: endocrinology
title Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator
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