Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity
Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transformation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divid...
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Veröffentlicht in: | Journal of medicinal chemistry 1993-10, Vol.36 (21), p.3137-3147 |
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creator | Asato, Alfred E Peng, Ao Hossain, Mohammad Z Mirzadegan, Taraneh Bertram, John S |
description | Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transformation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divided into two groups: compounds 1-6 were modeled after retinoic acid with flexible polyenic side chain whereas retinoids 7-13 featured a benzoic acid moiety analogous to the prototypic retinobenzoate (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]benzoic acid (TTNPB). Within this latter group the side chains for compounds 7, 10, and 11 were attached at the 1-, 2-, and 8-positions of the azulenic terminus, respectively. Biological activities were determined for all the new compounds. Two of these novel retinoids, azulenic retinobenzoic acid derivatives 7 and 11, were completely effective inhibitors of transformation at 10(-6) M. The most active azulenic retinoids also enhanced gap junctional communication in untransformed cells; this was associated with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azulenic fluoro acid 5 was found to be more potent than the trifluoromethyl analog 6. Azulenic analogs with hydroxyl or carboxaldehyde side chain functional groups were ineffective transformation inhibitors. In general, azulenic retinobenzoic acid analogs structurally akin to TTNPB were more effective than flexible side chain analogs related to retinoic acid. |
doi_str_mv | 10.1021/jm00073a013 |
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The azulenic retinoids were divided into two groups: compounds 1-6 were modeled after retinoic acid with flexible polyenic side chain whereas retinoids 7-13 featured a benzoic acid moiety analogous to the prototypic retinobenzoate (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]benzoic acid (TTNPB). Within this latter group the side chains for compounds 7, 10, and 11 were attached at the 1-, 2-, and 8-positions of the azulenic terminus, respectively. Biological activities were determined for all the new compounds. Two of these novel retinoids, azulenic retinobenzoic acid derivatives 7 and 11, were completely effective inhibitors of transformation at 10(-6) M. The most active azulenic retinoids also enhanced gap junctional communication in untransformed cells; this was associated with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azulenic fluoro acid 5 was found to be more potent than the trifluoromethyl analog 6. Azulenic analogs with hydroxyl or carboxaldehyde side chain functional groups were ineffective transformation inhibitors. In general, azulenic retinobenzoic acid analogs structurally akin to TTNPB were more effective than flexible side chain analogs related to retinoic acid.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00073a013</identifier><identifier>PMID: 8230100</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Azulenes ; Cells, Cultured ; Chemistry ; Computer Simulation ; Condensed benzenic and aromatic compounds ; Cycloheptanes - chemical synthesis ; Cycloheptanes - chemistry ; Cycloheptanes - pharmacology ; Exact sciences and technology ; Gap Junctions - drug effects ; Mice ; Mice, Inbred C3H ; Models, Molecular ; Organic chemistry ; Preparations and properties ; Retinoids - chemical synthesis ; Retinoids - chemistry ; Retinoids - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1993-10, Vol.36 (21), p.3137-3147</ispartof><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-125f472a24b51c224eeb25d183faba2b024e0caae08cfded558df43c05aaf2333</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00073a013$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00073a013$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3799573$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8230100$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Asato, Alfred E</creatorcontrib><creatorcontrib>Peng, Ao</creatorcontrib><creatorcontrib>Hossain, Mohammad Z</creatorcontrib><creatorcontrib>Mirzadegan, Taraneh</creatorcontrib><creatorcontrib>Bertram, John S</creatorcontrib><title>Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transformation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divided into two groups: compounds 1-6 were modeled after retinoic acid with flexible polyenic side chain whereas retinoids 7-13 featured a benzoic acid moiety analogous to the prototypic retinobenzoate (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]benzoic acid (TTNPB). Within this latter group the side chains for compounds 7, 10, and 11 were attached at the 1-, 2-, and 8-positions of the azulenic terminus, respectively. Biological activities were determined for all the new compounds. Two of these novel retinoids, azulenic retinobenzoic acid derivatives 7 and 11, were completely effective inhibitors of transformation at 10(-6) M. The most active azulenic retinoids also enhanced gap junctional communication in untransformed cells; this was associated with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azulenic fluoro acid 5 was found to be more potent than the trifluoromethyl analog 6. Azulenic analogs with hydroxyl or carboxaldehyde side chain functional groups were ineffective transformation inhibitors. In general, azulenic retinobenzoic acid analogs structurally akin to TTNPB were more effective than flexible side chain analogs related to retinoic acid.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Azulenes</subject><subject>Cells, Cultured</subject><subject>Chemistry</subject><subject>Computer Simulation</subject><subject>Condensed benzenic and aromatic compounds</subject><subject>Cycloheptanes - chemical synthesis</subject><subject>Cycloheptanes - chemistry</subject><subject>Cycloheptanes - pharmacology</subject><subject>Exact sciences and technology</subject><subject>Gap Junctions - drug effects</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Models, Molecular</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Retinoids - chemical synthesis</subject><subject>Retinoids - chemistry</subject><subject>Retinoids - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1LAzEQxYMoWj9OnoU9CB5kdTLZdLfeRK0VC4of9Rhms1lMbXdLsq22f70pLcWDlxl478dj5jF2zOGCA_LL4RgAUkHAxRZrcYkQJxkk26wFgBhjG8Ue2_d-GDDBUeyy3QwFcIAWe7leTEemsjpyprFVbQt_FVX1zIzCrHJTLcxSjMjVY2r-YtG3bT4jqoJIlTYuIt3YmW3mh2ynpJE3R-t9wN67d283vbj_dP9wc92PSWSiiTnKMkmRMMkl14iJMTnKgmeipJwwh6CAJjKQ6bIwhZRZUSZCgyQqUQhxwM5XudrV3jtTqomzY3JzxUEti1F_ign0yYqeTPOxKTbsuongn6598ppGpQtPWb_BRNrpyHQZE68w6xvzs7HJfal2KlKp3p5fVW_wOnjs3qL6CPzZiift1bCeuipU8u-BvyjXiAk</recordid><startdate>19931015</startdate><enddate>19931015</enddate><creator>Asato, Alfred E</creator><creator>Peng, Ao</creator><creator>Hossain, Mohammad Z</creator><creator>Mirzadegan, Taraneh</creator><creator>Bertram, John S</creator><general>American Chemical Society</general><scope>BSCLL</scope><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></search><sort><creationdate>19931015</creationdate><title>Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity</title><author>Asato, Alfred E ; Peng, Ao ; Hossain, Mohammad Z ; Mirzadegan, Taraneh ; Bertram, John S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-125f472a24b51c224eeb25d183faba2b024e0caae08cfded558df43c05aaf2333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemistry</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Azulenes</topic><topic>Cells, Cultured</topic><topic>Chemistry</topic><topic>Computer Simulation</topic><topic>Condensed benzenic and aromatic compounds</topic><topic>Cycloheptanes - chemical synthesis</topic><topic>Cycloheptanes - chemistry</topic><topic>Cycloheptanes - pharmacology</topic><topic>Exact sciences and technology</topic><topic>Gap Junctions - drug effects</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Models, Molecular</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Retinoids - chemical synthesis</topic><topic>Retinoids - chemistry</topic><topic>Retinoids - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Asato, Alfred E</creatorcontrib><creatorcontrib>Peng, Ao</creatorcontrib><creatorcontrib>Hossain, Mohammad Z</creatorcontrib><creatorcontrib>Mirzadegan, Taraneh</creatorcontrib><creatorcontrib>Bertram, John S</creatorcontrib><collection>Istex</collection><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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Asato, Alfred E</au><au>Peng, Ao</au><au>Hossain, Mohammad Z</au><au>Mirzadegan, Taraneh</au><au>Bertram, John S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1993-10-15</date><risdate>1993</risdate><volume>36</volume><issue>21</issue><spage>3137</spage><epage>3147</epage><pages>3137-3147</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transformation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divided into two groups: compounds 1-6 were modeled after retinoic acid with flexible polyenic side chain whereas retinoids 7-13 featured a benzoic acid moiety analogous to the prototypic retinobenzoate (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]benzoic acid (TTNPB). Within this latter group the side chains for compounds 7, 10, and 11 were attached at the 1-, 2-, and 8-positions of the azulenic terminus, respectively. Biological activities were determined for all the new compounds. Two of these novel retinoids, azulenic retinobenzoic acid derivatives 7 and 11, were completely effective inhibitors of transformation at 10(-6) M. The most active azulenic retinoids also enhanced gap junctional communication in untransformed cells; this was associated with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azulenic fluoro acid 5 was found to be more potent than the trifluoromethyl analog 6. Azulenic analogs with hydroxyl or carboxaldehyde side chain functional groups were ineffective transformation inhibitors. In general, azulenic retinobenzoic acid analogs structurally akin to TTNPB were more effective than flexible side chain analogs related to retinoic acid.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8230100</pmid><doi>10.1021/jm00073a013</doi><tpages>11</tpages></addata></record> |
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subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Azulenes Cells, Cultured Chemistry Computer Simulation Condensed benzenic and aromatic compounds Cycloheptanes - chemical synthesis Cycloheptanes - chemistry Cycloheptanes - pharmacology Exact sciences and technology Gap Junctions - drug effects Mice Mice, Inbred C3H Models, Molecular Organic chemistry Preparations and properties Retinoids - chemical synthesis Retinoids - chemistry Retinoids - pharmacology Structure-Activity Relationship |
title | Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity |
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