Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents
[(μ4-η2)-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and clu...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-10, Vol.53 (19), p.6889-6898 |
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| creator | Rubner, Gerhard Bensdorf, Kerstin Wellner, Anja Kircher, Brigitte Bergemann, Silke Ott, Ingo Gust, Ronald |
| description | [(μ4-η2)-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure−activity study: Co2(CO)6 was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE2) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co 4 and Prop-ASS-Ru 3 correlated well with apoptosis induction. |
| doi_str_mv | 10.1021/jm101019j |
| format | Article |
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The significance of the kind of metal and cluster was verified in this structure−activity study: Co2(CO)6 was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE2) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co 4 and Prop-ASS-Ru 3 correlated well with apoptosis induction.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm101019j</identifier><identifier>PMID: 20857911</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alkynes - chemical synthesis ; Alkynes - pharmacology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Arachidonic Acid - pharmacology ; Aspirin - analogs & derivatives ; Aspirin - chemical synthesis ; Aspirin - pharmacology ; Butadienes - chemical synthesis ; Butadienes - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cobalt ; Coordination Complexes - chemical synthesis ; Coordination Complexes - pharmacology ; Cyclooxygenase Inhibitors - chemical synthesis ; Cyclooxygenase Inhibitors - pharmacology ; Dinoprostone - metabolism ; Drug Screening Assays, Antitumor ; Humans ; Iron ; Ruthenium ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2010-10, Vol.53 (19), p.6889-6898</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-cdd45d50d9fdbba92db1e25661d6153f522168767e52238086335b93bb2b2af73</citedby><cites>FETCH-LOGICAL-a314t-cdd45d50d9fdbba92db1e25661d6153f522168767e52238086335b93bb2b2af73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm101019j$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm101019j$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20857911$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rubner, Gerhard</creatorcontrib><creatorcontrib>Bensdorf, Kerstin</creatorcontrib><creatorcontrib>Wellner, Anja</creatorcontrib><creatorcontrib>Kircher, Brigitte</creatorcontrib><creatorcontrib>Bergemann, Silke</creatorcontrib><creatorcontrib>Ott, Ingo</creatorcontrib><creatorcontrib>Gust, Ronald</creatorcontrib><title>Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>[(μ4-η2)-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure−activity study: Co2(CO)6 was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE2) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co 4 and Prop-ASS-Ru 3 correlated well with apoptosis induction.</description><subject>Alkynes - chemical synthesis</subject><subject>Alkynes - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Arachidonic Acid - pharmacology</subject><subject>Aspirin - analogs & derivatives</subject><subject>Aspirin - chemical synthesis</subject><subject>Aspirin - pharmacology</subject><subject>Butadienes - chemical synthesis</subject><subject>Butadienes - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cobalt</subject><subject>Coordination Complexes - chemical synthesis</subject><subject>Coordination Complexes - pharmacology</subject><subject>Cyclooxygenase Inhibitors - chemical synthesis</subject><subject>Cyclooxygenase Inhibitors - pharmacology</subject><subject>Dinoprostone - metabolism</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Iron</subject><subject>Ruthenium</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1rGzEQhkVIiR23h_yBoksIOWyrj9V-HNemTQpue2h6XrTSbCKzK7k7crD_fWWc5BSGYWZ4H16Yl5Arzr5wJvjXzchZqnpzRuZcCZblFcvPyZwxITJRCDkjl4gbxpjkQl6QmWCVKmvO52T_5-DjE6BDqr2lSxeG8OiMHmhjont20QHS0NOHSXtMV_D0J8Qkr8K4HWCf1KVGsDQJjYF4GFAPzhxSp9tZqpH-gpA1PiZXb2CizSP4iB_Jh14PCJ9e5oL8_f7tYXWfrX_f_Vg160xLnsfMWJsrq5ite9t1uha24yBUUXBbcCV7JQQvqrIoIW2yYlUhpepq2XWiE7ov5YLcnHy3U_i3A4zt6NDAMGgPYYdtqUpeljk_krcn0kwBcYK-3U5u1NOh5aw95ty-5ZzYzy-uu24E-0a-BpuA6xOgDbabsJt8evIdo_99BYSH</recordid><startdate>20101014</startdate><enddate>20101014</enddate><creator>Rubner, Gerhard</creator><creator>Bensdorf, Kerstin</creator><creator>Wellner, Anja</creator><creator>Kircher, Brigitte</creator><creator>Bergemann, Silke</creator><creator>Ott, Ingo</creator><creator>Gust, Ronald</creator><general>American Chemical Society</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>20101014</creationdate><title>Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents</title><author>Rubner, Gerhard ; Bensdorf, Kerstin ; Wellner, Anja ; Kircher, Brigitte ; Bergemann, Silke ; Ott, Ingo ; Gust, Ronald</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-cdd45d50d9fdbba92db1e25661d6153f522168767e52238086335b93bb2b2af73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alkynes - chemical synthesis</topic><topic>Alkynes - pharmacology</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Arachidonic Acid - pharmacology</topic><topic>Aspirin - analogs & derivatives</topic><topic>Aspirin - chemical synthesis</topic><topic>Aspirin - pharmacology</topic><topic>Butadienes - chemical synthesis</topic><topic>Butadienes - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cobalt</topic><topic>Coordination Complexes - chemical synthesis</topic><topic>Coordination Complexes - pharmacology</topic><topic>Cyclooxygenase Inhibitors - chemical synthesis</topic><topic>Cyclooxygenase Inhibitors - pharmacology</topic><topic>Dinoprostone - metabolism</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Iron</topic><topic>Ruthenium</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rubner, Gerhard</creatorcontrib><creatorcontrib>Bensdorf, Kerstin</creatorcontrib><creatorcontrib>Wellner, Anja</creatorcontrib><creatorcontrib>Kircher, Brigitte</creatorcontrib><creatorcontrib>Bergemann, Silke</creatorcontrib><creatorcontrib>Ott, Ingo</creatorcontrib><creatorcontrib>Gust, Ronald</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rubner, Gerhard</au><au>Bensdorf, Kerstin</au><au>Wellner, Anja</au><au>Kircher, Brigitte</au><au>Bergemann, Silke</au><au>Ott, Ingo</au><au>Gust, Ronald</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-10-14</date><risdate>2010</risdate><volume>53</volume><issue>19</issue><spage>6889</spage><epage>6898</epage><pages>6889-6898</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>[(μ4-η2)-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure−activity study: Co2(CO)6 was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE2) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co 4 and Prop-ASS-Ru 3 correlated well with apoptosis induction.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20857911</pmid><doi>10.1021/jm101019j</doi><tpages>10</tpages></addata></record> |
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| subjects | Alkynes - chemical synthesis Alkynes - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Arachidonic Acid - pharmacology Aspirin - analogs & derivatives Aspirin - chemical synthesis Aspirin - pharmacology Butadienes - chemical synthesis Butadienes - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Cobalt Coordination Complexes - chemical synthesis Coordination Complexes - pharmacology Cyclooxygenase Inhibitors - chemical synthesis Cyclooxygenase Inhibitors - pharmacology Dinoprostone - metabolism Drug Screening Assays, Antitumor Humans Iron Ruthenium Stereoisomerism Structure-Activity Relationship |
| title | Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents |
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