A-ring bridged steroids as potent inhibitors of aromatase
The design and syntheses of androstenedione derivatives with bridges spanning the 2,19-, 3,19-, 4,19- and 6,19-positions are described. 2,19-Bridged compounds bearing hydroxyl groups on the two-carbon bridge ( 3a and 3b) were designed as stable carbon analogs of potential lactol intermediates in the...
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| Veröffentlicht in: | Journal of steroid biochemistry and molecular biology 1993-03, Vol.44 (4), p.409-420 |
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| container_end_page | 420 |
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| container_issue | 4 |
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| container_title | Journal of steroid biochemistry and molecular biology |
| container_volume | 44 |
| creator | Peet, Norton P. Johnston, J.O'Neal Burkhart, Joseph P. Wright, C.Lee |
| description | The design and syntheses of androstenedione derivatives with bridges spanning the 2,19-, 3,19-, 4,19- and 6,19-positions are described. 2,19-Bridged compounds bearing hydroxyl groups on the two-carbon bridge (
3a and
3b) were designed as stable carbon analogs of potential lactol intermediates in the enzymatic conversion of androgens to estrogens. Compounds
3a and
3b are competitive inhibitors of aromatase. Pyran
25 is a potent, time-dependent inhibitor of aromatase with partial NADPH dependence. These data suggest a mechanism of inhibition for
25 which involves both tight-binding competitive and mechanism-based components, with the former predominating. The sulfur, amino, and all carbon analogs of pyran
25 were prepared. Thiopyran
36, piperidine
42 and the all-carbon analog
47 are also time-dependent inhibitors of aromatase. Compound
47 is the most potent inhibitor and its time-dependent inhibition is not NADPH dependent. The kinetics of piperidine
42 suggest uncompetitive inhibition. |
| doi_str_mv | 10.1016/0960-0760(93)90244-Q |
| format | Article |
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3a and
3b) were designed as stable carbon analogs of potential lactol intermediates in the enzymatic conversion of androgens to estrogens. Compounds
3a and
3b are competitive inhibitors of aromatase. Pyran
25 is a potent, time-dependent inhibitor of aromatase with partial NADPH dependence. These data suggest a mechanism of inhibition for
25 which involves both tight-binding competitive and mechanism-based components, with the former predominating. The sulfur, amino, and all carbon analogs of pyran
25 were prepared. Thiopyran
36, piperidine
42 and the all-carbon analog
47 are also time-dependent inhibitors of aromatase. Compound
47 is the most potent inhibitor and its time-dependent inhibition is not NADPH dependent. The kinetics of piperidine
42 suggest uncompetitive inhibition.</description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/0960-0760(93)90244-Q</identifier><identifier>PMID: 8476754</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Aromatase Inhibitors ; Biological and medical sciences ; General pharmacology ; Humans ; Kinetics ; Medical sciences ; Molecular Structure ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. Drug treatments ; Stereoisomerism ; Steroids - chemical synthesis ; Steroids - chemistry ; Steroids - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of steroid biochemistry and molecular biology, 1993-03, Vol.44 (4), p.409-420</ispartof><rights>1993</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-2f93803c4ea4f427413ebe56e7f5a226baac2de616d130476bf2fea2e58a81a03</citedby><cites>FETCH-LOGICAL-c386t-2f93803c4ea4f427413ebe56e7f5a226baac2de616d130476bf2fea2e58a81a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/096007609390244Q$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>309,310,314,776,780,785,786,3537,23909,23910,25118,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4693132$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8476754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Peet, Norton P.</creatorcontrib><creatorcontrib>Johnston, J.O'Neal</creatorcontrib><creatorcontrib>Burkhart, Joseph P.</creatorcontrib><creatorcontrib>Wright, C.Lee</creatorcontrib><title>A-ring bridged steroids as potent inhibitors of aromatase</title><title>Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>The design and syntheses of androstenedione derivatives with bridges spanning the 2,19-, 3,19-, 4,19- and 6,19-positions are described. 2,19-Bridged compounds bearing hydroxyl groups on the two-carbon bridge (
3a and
3b) were designed as stable carbon analogs of potential lactol intermediates in the enzymatic conversion of androgens to estrogens. Compounds
3a and
3b are competitive inhibitors of aromatase. Pyran
25 is a potent, time-dependent inhibitor of aromatase with partial NADPH dependence. These data suggest a mechanism of inhibition for
25 which involves both tight-binding competitive and mechanism-based components, with the former predominating. The sulfur, amino, and all carbon analogs of pyran
25 were prepared. Thiopyran
36, piperidine
42 and the all-carbon analog
47 are also time-dependent inhibitors of aromatase. Compound
47 is the most potent inhibitor and its time-dependent inhibition is not NADPH dependent. The kinetics of piperidine
42 suggest uncompetitive inhibition.</description><subject>Aromatase Inhibitors</subject><subject>Biological and medical sciences</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Stereoisomerism</subject><subject>Steroids - chemical synthesis</subject><subject>Steroids - chemistry</subject><subject>Steroids - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLAzEUhYMotVb_gcIsRHQxmtdkJhuhFF9QkIKuw53MTY20k5pMBf-9U1u6dHUX5zuHy0fIOaO3jDJ1R7WiOS0VvdbiRlMuZT47IENWlTpnnNNDMtwjx-QkpU9KqRCsHJBBJUtVFnJI9DiPvp1ndfTNHJssdRiDb1IGKVuFDtsu8-2Hr30XYsqCyyCGJXSQ8JQcOVgkPNvdEXl_fHibPOfT16eXyXiaW1GpLudOi4oKKxGkk7yUTGCNhcLSFcC5qgEsb1Ax1TBB-7dqxx0Cx6KCigEVI3K13V3F8LXG1JmlTxYXC2gxrJMpC1VxzaselFvQxpBSRGdW0S8h_hhGzcaY2egwGx1GC_NnzMz62sVuf10vsdmXdor6_HKXQ7KwcBFa69Mek0oLJniP3W8x7F18e4wmWY-txcZHtJ1pgv__j1_HJIax</recordid><startdate>19930301</startdate><enddate>19930301</enddate><creator>Peet, Norton P.</creator><creator>Johnston, J.O'Neal</creator><creator>Burkhart, Joseph P.</creator><creator>Wright, C.Lee</creator><general>Elsevier Ltd</general><general>Elsevier Science</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>19930301</creationdate><title>A-ring bridged steroids as potent inhibitors of aromatase</title><author>Peet, Norton P. ; Johnston, J.O'Neal ; Burkhart, Joseph P. ; Wright, C.Lee</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-2f93803c4ea4f427413ebe56e7f5a226baac2de616d130476bf2fea2e58a81a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Aromatase Inhibitors</topic><topic>Biological and medical sciences</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Stereoisomerism</topic><topic>Steroids - chemical synthesis</topic><topic>Steroids - chemistry</topic><topic>Steroids - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peet, Norton P.</creatorcontrib><creatorcontrib>Johnston, J.O'Neal</creatorcontrib><creatorcontrib>Burkhart, Joseph P.</creatorcontrib><creatorcontrib>Wright, C.Lee</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>Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peet, Norton P.</au><au>Johnston, J.O'Neal</au><au>Burkhart, Joseph P.</au><au>Wright, C.Lee</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A-ring bridged steroids as potent inhibitors of aromatase</atitle><jtitle>Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>1993-03-01</date><risdate>1993</risdate><volume>44</volume><issue>4</issue><spage>409</spage><epage>420</epage><pages>409-420</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract>The design and syntheses of androstenedione derivatives with bridges spanning the 2,19-, 3,19-, 4,19- and 6,19-positions are described. 2,19-Bridged compounds bearing hydroxyl groups on the two-carbon bridge (
3a and
3b) were designed as stable carbon analogs of potential lactol intermediates in the enzymatic conversion of androgens to estrogens. Compounds
3a and
3b are competitive inhibitors of aromatase. Pyran
25 is a potent, time-dependent inhibitor of aromatase with partial NADPH dependence. These data suggest a mechanism of inhibition for
25 which involves both tight-binding competitive and mechanism-based components, with the former predominating. The sulfur, amino, and all carbon analogs of pyran
25 were prepared. Thiopyran
36, piperidine
42 and the all-carbon analog
47 are also time-dependent inhibitors of aromatase. Compound
47 is the most potent inhibitor and its time-dependent inhibition is not NADPH dependent. The kinetics of piperidine
42 suggest uncompetitive inhibition.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>8476754</pmid><doi>10.1016/0960-0760(93)90244-Q</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-0760 |
| ispartof | Journal of steroid biochemistry and molecular biology, 1993-03, Vol.44 (4), p.409-420 |
| issn | 0960-0760 1879-1220 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Aromatase Inhibitors Biological and medical sciences General pharmacology Humans Kinetics Medical sciences Molecular Structure Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Stereoisomerism Steroids - chemical synthesis Steroids - chemistry Steroids - pharmacology Structure-Activity Relationship |
| title | A-ring bridged steroids as potent inhibitors of aromatase |
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