Diethylstilbestrol-scaffold-based pregnane X receptor modulators
Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroid...
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Veröffentlicht in: | European journal of medicinal chemistry 2015-10, Vol.103, p.551-562 |
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container_title | European journal of medicinal chemistry |
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creator | Hodnik, Žiga Tomašič, Tihomir Smodiš, Domen D'Amore, Claudio Mašič, Lucija Peterlin Fiorucci, Stefano Kikelj, Danijel |
description | Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroids with PXR agonistic activity, solomonsterols A and B, and our recently reported bazedoxifene scaffold-derived PXR antagonists. The methylated diethylstilbestrol derivative 1 displayed potent PXR agonistic activity with an EC50 value of 10.5 μM, whereas compounds 3, 4 and 6 (IC50 for 6 = 27.4 μM) and diethylstilbestrol (2) itself (IC50 = 14.6 μM) exhibited PXR antagonistic effects in HepG2 cells. The PXR modulatory effects of the synthesized diethylstilbestrol derivatives were further confirmed by the induction of PXR-regulated CYP3A4 expression with compound 1, as well as by the inhibition of the rifaximin-promoted up-regulation of CYP3A4 expression with 2 and its derivative 6.
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•A series of DES-based solomonsterol A and B analogs was synthesized.•The PXR modulatory activity of the compounds was evaluated.•The methylated DES derivative 1 showed PXR agonistic activity with EC50 of 10.5 μM.•DES and its analogs 3, 4 and 6 showed PXR antagonistic activity.•Compound 6 inhibited rifaximin-promoted up-regulation of CYP3A4 expression. |
doi_str_mv | 10.1016/j.ejmech.2015.09.005 |
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[Display omitted]
•A series of DES-based solomonsterol A and B analogs was synthesized.•The PXR modulatory activity of the compounds was evaluated.•The methylated DES derivative 1 showed PXR agonistic activity with EC50 of 10.5 μM.•DES and its analogs 3, 4 and 6 showed PXR antagonistic activity.•Compound 6 inhibited rifaximin-promoted up-regulation of CYP3A4 expression.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2015.09.005</identifier><identifier>PMID: 26408814</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Cytochrome P-450 CYP3A - biosynthesis ; Cytochrome P-450 CYP3A - metabolism ; Diethylstilbestrol ; Diethylstilbestrol - chemical synthesis ; Diethylstilbestrol - chemistry ; Diethylstilbestrol - pharmacology ; Dose-Response Relationship, Drug ; Drug Design ; Hep G2 Cells ; Humans ; Mimetic ; Models, Molecular ; Molecular Structure ; Pregnane X Receptor ; PXR agonist ; PXR antagonist ; Receptors, Steroid - agonists ; Receptors, Steroid - antagonists & inhibitors ; Rifamycins - antagonists & inhibitors ; Rifamycins - pharmacology ; Rifaximin ; Solomonsterol ; Structure-Activity Relationship ; Up-Regulation - drug effects</subject><ispartof>European journal of medicinal chemistry, 2015-10, Vol.103, p.551-562</ispartof><rights>2015 Elsevier Masson SAS</rights><rights>Copyright © 2015 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-95ae0d106ae2e5de8c98b5762d7d928a6766df9ce04d08b1fdb27e0536e19fe23</citedby><cites>FETCH-LOGICAL-c362t-95ae0d106ae2e5de8c98b5762d7d928a6766df9ce04d08b1fdb27e0536e19fe23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2015.09.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26408814$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hodnik, Žiga</creatorcontrib><creatorcontrib>Tomašič, Tihomir</creatorcontrib><creatorcontrib>Smodiš, Domen</creatorcontrib><creatorcontrib>D'Amore, Claudio</creatorcontrib><creatorcontrib>Mašič, Lucija Peterlin</creatorcontrib><creatorcontrib>Fiorucci, Stefano</creatorcontrib><creatorcontrib>Kikelj, Danijel</creatorcontrib><title>Diethylstilbestrol-scaffold-based pregnane X receptor modulators</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroids with PXR agonistic activity, solomonsterols A and B, and our recently reported bazedoxifene scaffold-derived PXR antagonists. The methylated diethylstilbestrol derivative 1 displayed potent PXR agonistic activity with an EC50 value of 10.5 μM, whereas compounds 3, 4 and 6 (IC50 for 6 = 27.4 μM) and diethylstilbestrol (2) itself (IC50 = 14.6 μM) exhibited PXR antagonistic effects in HepG2 cells. The PXR modulatory effects of the synthesized diethylstilbestrol derivatives were further confirmed by the induction of PXR-regulated CYP3A4 expression with compound 1, as well as by the inhibition of the rifaximin-promoted up-regulation of CYP3A4 expression with 2 and its derivative 6.
[Display omitted]
•A series of DES-based solomonsterol A and B analogs was synthesized.•The PXR modulatory activity of the compounds was evaluated.•The methylated DES derivative 1 showed PXR agonistic activity with EC50 of 10.5 μM.•DES and its analogs 3, 4 and 6 showed PXR antagonistic activity.•Compound 6 inhibited rifaximin-promoted up-regulation of CYP3A4 expression.</description><subject>Cytochrome P-450 CYP3A - biosynthesis</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Diethylstilbestrol</subject><subject>Diethylstilbestrol - chemical synthesis</subject><subject>Diethylstilbestrol - chemistry</subject><subject>Diethylstilbestrol - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Mimetic</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Pregnane X Receptor</subject><subject>PXR agonist</subject><subject>PXR antagonist</subject><subject>Receptors, Steroid - agonists</subject><subject>Receptors, Steroid - antagonists & inhibitors</subject><subject>Rifamycins - antagonists & inhibitors</subject><subject>Rifamycins - pharmacology</subject><subject>Rifaximin</subject><subject>Solomonsterol</subject><subject>Structure-Activity Relationship</subject><subject>Up-Regulation - drug effects</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1PwzAQhi0EoqXwDxDqyJJwdmwnWRCofEqVWEBisxz7QhMlTbATpP57jFIYme6G572Ph5BzCjEFKq_qGOsWzSZmQEUMeQwgDsicpjKLEib4IZkDY0kkWMJn5MT7GgIhAY7JjEkOWUb5nNzcVThsdo0fqqZAP7iuibzRZdk1Niq0R7vsHX5s9RaX70uHBvuhc8u2s2OjQ-dPyVGpG49n-7ogbw_3r6unaP3y-Ly6XUcmkWyIcqERLAWpkaGwmJk8K0QqmU1tzjItUyltmRsEbiEraGkLliKIRCLNS2TJglxOc3vXfY7hUtVW3mDThMu60SuaMprwlFMRUD6hxnXeOyxV76pWu52ioH7cqVpN7tSPOwW5CmZC7GK_YSxatH-hX1kBuJ4ADH9-VeiUNxVuDdoqiBmU7ar_N3wD7DKCTw</recordid><startdate>20151020</startdate><enddate>20151020</enddate><creator>Hodnik, Žiga</creator><creator>Tomašič, Tihomir</creator><creator>Smodiš, Domen</creator><creator>D'Amore, Claudio</creator><creator>Mašič, Lucija Peterlin</creator><creator>Fiorucci, Stefano</creator><creator>Kikelj, Danijel</creator><general>Elsevier Masson SAS</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></search><sort><creationdate>20151020</creationdate><title>Diethylstilbestrol-scaffold-based pregnane X receptor modulators</title><author>Hodnik, Žiga ; Tomašič, Tihomir ; Smodiš, Domen ; D'Amore, Claudio ; Mašič, Lucija Peterlin ; Fiorucci, Stefano ; Kikelj, Danijel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-95ae0d106ae2e5de8c98b5762d7d928a6766df9ce04d08b1fdb27e0536e19fe23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Cytochrome P-450 CYP3A - biosynthesis</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Diethylstilbestrol</topic><topic>Diethylstilbestrol - chemical synthesis</topic><topic>Diethylstilbestrol - chemistry</topic><topic>Diethylstilbestrol - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Mimetic</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Pregnane X Receptor</topic><topic>PXR agonist</topic><topic>PXR antagonist</topic><topic>Receptors, Steroid - agonists</topic><topic>Receptors, Steroid - antagonists & inhibitors</topic><topic>Rifamycins - antagonists & inhibitors</topic><topic>Rifamycins - pharmacology</topic><topic>Rifaximin</topic><topic>Solomonsterol</topic><topic>Structure-Activity Relationship</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hodnik, Žiga</creatorcontrib><creatorcontrib>Tomašič, Tihomir</creatorcontrib><creatorcontrib>Smodiš, Domen</creatorcontrib><creatorcontrib>D'Amore, Claudio</creatorcontrib><creatorcontrib>Mašič, Lucija Peterlin</creatorcontrib><creatorcontrib>Fiorucci, Stefano</creatorcontrib><creatorcontrib>Kikelj, Danijel</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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hodnik, Žiga</au><au>Tomašič, Tihomir</au><au>Smodiš, Domen</au><au>D'Amore, Claudio</au><au>Mašič, Lucija Peterlin</au><au>Fiorucci, Stefano</au><au>Kikelj, Danijel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diethylstilbestrol-scaffold-based pregnane X receptor modulators</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2015-10-20</date><risdate>2015</risdate><volume>103</volume><spage>551</spage><epage>562</epage><pages>551-562</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroids with PXR agonistic activity, solomonsterols A and B, and our recently reported bazedoxifene scaffold-derived PXR antagonists. The methylated diethylstilbestrol derivative 1 displayed potent PXR agonistic activity with an EC50 value of 10.5 μM, whereas compounds 3, 4 and 6 (IC50 for 6 = 27.4 μM) and diethylstilbestrol (2) itself (IC50 = 14.6 μM) exhibited PXR antagonistic effects in HepG2 cells. The PXR modulatory effects of the synthesized diethylstilbestrol derivatives were further confirmed by the induction of PXR-regulated CYP3A4 expression with compound 1, as well as by the inhibition of the rifaximin-promoted up-regulation of CYP3A4 expression with 2 and its derivative 6.
[Display omitted]
•A series of DES-based solomonsterol A and B analogs was synthesized.•The PXR modulatory activity of the compounds was evaluated.•The methylated DES derivative 1 showed PXR agonistic activity with EC50 of 10.5 μM.•DES and its analogs 3, 4 and 6 showed PXR antagonistic activity.•Compound 6 inhibited rifaximin-promoted up-regulation of CYP3A4 expression.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>26408814</pmid><doi>10.1016/j.ejmech.2015.09.005</doi><tpages>12</tpages></addata></record> |
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subjects | Cytochrome P-450 CYP3A - biosynthesis Cytochrome P-450 CYP3A - metabolism Diethylstilbestrol Diethylstilbestrol - chemical synthesis Diethylstilbestrol - chemistry Diethylstilbestrol - pharmacology Dose-Response Relationship, Drug Drug Design Hep G2 Cells Humans Mimetic Models, Molecular Molecular Structure Pregnane X Receptor PXR agonist PXR antagonist Receptors, Steroid - agonists Receptors, Steroid - antagonists & inhibitors Rifamycins - antagonists & inhibitors Rifamycins - pharmacology Rifaximin Solomonsterol Structure-Activity Relationship Up-Regulation - drug effects |
title | Diethylstilbestrol-scaffold-based pregnane X receptor modulators |
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