Synthesis, Characterization, and in Vitro Studies of Bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I/III) Complexes
Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4-OCH3 or 4-F substituents in the aromatic rings and Br– (3a,b) or BF4 – (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-he...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-04, Vol.55 (8), p.3713-3724 |
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| container_title | Journal of medicinal chemistry |
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| creator | Liu, Wukun Bensdorf, Kerstin Proetto, Maria Hagenbach, Adelheid Abram, Ulrich Gust, Ronald |
| description | Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4-OCH3 or 4-F substituents in the aromatic rings and Br– (3a,b) or BF4 – (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC50 = 0.10 μM (cisplatin, 1.6 μM; 5-FU, 4.7 μM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action. |
| doi_str_mv | 10.1021/jm3000196 |
| format | Article |
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Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC50 = 0.10 μM (cisplatin, 1.6 μM; 5-FU, 4.7 μM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm3000196</identifier><identifier>PMID: 22424185</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Auranofin - analogs & derivatives ; Cell Line, Tumor ; Crystallography, X-Ray ; Cyclooxygenase Inhibitors - pharmacology ; Glutathione - metabolism ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - metabolism ; Imidazoles - pharmacology ; Inhibitory Concentration 50 ; Organogold Compounds - chemical synthesis ; Organogold Compounds - metabolism ; Organogold Compounds - pharmacology ; Structure-Activity Relationship ; Thioredoxin-Disulfide Reductase - antagonists & inhibitors</subject><ispartof>Journal of medicinal chemistry, 2012-04, Vol.55 (8), p.3713-3724</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-5351977a6ce8ce3166162a0a5e21ec2962404da28f2cf2d60d3e7a4dfddec3553</citedby><cites>FETCH-LOGICAL-a315t-5351977a6ce8ce3166162a0a5e21ec2962404da28f2cf2d60d3e7a4dfddec3553</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/jm3000196$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm3000196$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22424185$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Wukun</creatorcontrib><creatorcontrib>Bensdorf, Kerstin</creatorcontrib><creatorcontrib>Proetto, Maria</creatorcontrib><creatorcontrib>Hagenbach, Adelheid</creatorcontrib><creatorcontrib>Abram, Ulrich</creatorcontrib><creatorcontrib>Gust, Ronald</creatorcontrib><title>Synthesis, Characterization, and in Vitro Studies of Bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I/III) Complexes</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4-OCH3 or 4-F substituents in the aromatic rings and Br– (3a,b) or BF4 – (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC50 = 0.10 μM (cisplatin, 1.6 μM; 5-FU, 4.7 μM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Auranofin - analogs & derivatives</subject><subject>Cell Line, Tumor</subject><subject>Crystallography, X-Ray</subject><subject>Cyclooxygenase Inhibitors - pharmacology</subject><subject>Glutathione - metabolism</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - metabolism</subject><subject>Imidazoles - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Organogold Compounds - chemical synthesis</subject><subject>Organogold Compounds - metabolism</subject><subject>Organogold Compounds - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Thioredoxin-Disulfide Reductase - antagonists & inhibitors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EFr2zAUB3AxOtY07WFfYPhSSCBqpSdLcY5baFdDoYe2u4xiNOl5UbCtTLJZk09fjaQ57aT34MdfvD8hnzm74gz49boVjDG-UB_IiEtgNC9YfkJGjAFQUCBOyVmM62QEB_GJnALkkPNCjsjfx23XrzC6OMuWKx206TG4ne6d72aZ7mzmuuyH64PPHvvBOoyZr7NvLv7kM0HT3q-2Dc1nMs06bBvXOqt3vqFA02Kxw5ffvrGT8rosy2m29O2mwVeM5-RjrZuIF4d3TJ5vb56Wd_T-4Xu5_HpPteCyp1JIvpjPtTJYGBRcKa5AMy0ROBpYKMhZbjUUNZgarGJW4FzntrYWjZBSjMlkn7sJ_s-Asa9aFw02je7QD7FK_bFCpL9UotM9NcHHGLCuNsG16aiE_jleHXtO9sshdvjVoj3K92ITuNwDbWK19kPo0pX_CXoDKsCCng</recordid><startdate>20120426</startdate><enddate>20120426</enddate><creator>Liu, Wukun</creator><creator>Bensdorf, Kerstin</creator><creator>Proetto, Maria</creator><creator>Hagenbach, Adelheid</creator><creator>Abram, Ulrich</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>20120426</creationdate><title>Synthesis, Characterization, and in Vitro Studies of Bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I/III) Complexes</title><author>Liu, Wukun ; Bensdorf, Kerstin ; Proetto, Maria ; Hagenbach, Adelheid ; Abram, Ulrich ; Gust, Ronald</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-5351977a6ce8ce3166162a0a5e21ec2962404da28f2cf2d60d3e7a4dfddec3553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Auranofin - analogs & derivatives</topic><topic>Cell Line, Tumor</topic><topic>Crystallography, X-Ray</topic><topic>Cyclooxygenase Inhibitors - pharmacology</topic><topic>Glutathione - metabolism</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - metabolism</topic><topic>Imidazoles - pharmacology</topic><topic>Inhibitory Concentration 50</topic><topic>Organogold Compounds - chemical synthesis</topic><topic>Organogold Compounds - metabolism</topic><topic>Organogold Compounds - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Thioredoxin-Disulfide Reductase - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Wukun</creatorcontrib><creatorcontrib>Bensdorf, Kerstin</creatorcontrib><creatorcontrib>Proetto, Maria</creatorcontrib><creatorcontrib>Hagenbach, Adelheid</creatorcontrib><creatorcontrib>Abram, Ulrich</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>Liu, Wukun</au><au>Bensdorf, Kerstin</au><au>Proetto, Maria</au><au>Hagenbach, Adelheid</au><au>Abram, Ulrich</au><au>Gust, Ronald</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Characterization, and in Vitro Studies of Bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I/III) Complexes</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-04-26</date><risdate>2012</risdate><volume>55</volume><issue>8</issue><spage>3713</spage><epage>3724</epage><pages>3713-3724</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4-OCH3 or 4-F substituents in the aromatic rings and Br– (3a,b) or BF4 – (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC50 = 0.10 μM (cisplatin, 1.6 μM; 5-FU, 4.7 μM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22424185</pmid><doi>10.1021/jm3000196</doi><tpages>12</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Auranofin - analogs & derivatives Cell Line, Tumor Crystallography, X-Ray Cyclooxygenase Inhibitors - pharmacology Glutathione - metabolism Humans Imidazoles - chemical synthesis Imidazoles - metabolism Imidazoles - pharmacology Inhibitory Concentration 50 Organogold Compounds - chemical synthesis Organogold Compounds - metabolism Organogold Compounds - pharmacology Structure-Activity Relationship Thioredoxin-Disulfide Reductase - antagonists & inhibitors |
| title | Synthesis, Characterization, and in Vitro Studies of Bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I/III) Complexes |
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