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
Hauptverfasser: Asato, Alfred E, Peng, Ao, Hossain, Mohammad Z, Mirzadegan, Taraneh, Bertram, John S
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container_end_page 3147
container_issue 21
container_start_page 3137
container_title Journal of medicinal chemistry
container_volume 36
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 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. 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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. 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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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ispartof Journal of medicinal chemistry, 1993-10, Vol.36 (21), p.3137-3147
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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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