Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis
Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII 2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand),...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-06, Vol.67 (11), p.9091-9103 |
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| container_title | Journal of medicinal chemistry |
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| creator | Li, Aili Huang, Kai Pan, Weiping Wu, Youru Liang, Yuwei Zhang, ZhenLei Wu, Daqi Ma, Libing Gou, Yi |
| description | Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII 2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy. |
| doi_str_mv | 10.1021/acs.jmedchem.4c00257 |
| format | Article |
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In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII 2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c00257</identifier><identifier>PMID: 38778566</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>A549 Cells ; Adenocarcinoma - drug therapy ; Adenocarcinoma - pathology ; Adenocarcinoma of Lung - drug therapy ; Adenocarcinoma of Lung - pathology ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Coordination Complexes - chemical synthesis ; Coordination Complexes - chemistry ; Coordination Complexes - pharmacology ; Coordination Complexes - therapeutic use ; Copper - chemistry ; Drug Screening Assays, Antitumor ; Hemolysis - drug effects ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Signal Transduction - drug effects ; Structure-Activity Relationship ; Thiosemicarbazones - chemical synthesis ; Thiosemicarbazones - chemistry ; Thiosemicarbazones - pharmacology ; Thiosemicarbazones - therapeutic use ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2024-06, Vol.67 (11), p.9091-9103</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a297t-978475bb0fcfdf99668c927d589f5713c44d0c52b1dfed57779dfdf52bb122dd3</cites><orcidid>0000-0002-2900-4983</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.4c00257$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00257$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38778566$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Aili</creatorcontrib><creatorcontrib>Huang, Kai</creatorcontrib><creatorcontrib>Pan, Weiping</creatorcontrib><creatorcontrib>Wu, Youru</creatorcontrib><creatorcontrib>Liang, Yuwei</creatorcontrib><creatorcontrib>Zhang, ZhenLei</creatorcontrib><creatorcontrib>Wu, Daqi</creatorcontrib><creatorcontrib>Ma, Libing</creatorcontrib><creatorcontrib>Gou, Yi</creatorcontrib><title>Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII 2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.</description><subject>A549 Cells</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma of Lung - drug therapy</subject><subject>Adenocarcinoma of Lung - pathology</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Coordination Complexes - chemical synthesis</subject><subject>Coordination Complexes - chemistry</subject><subject>Coordination Complexes - pharmacology</subject><subject>Coordination Complexes - therapeutic use</subject><subject>Copper - chemistry</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Hemolysis - drug effects</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Signal Transduction - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Thiosemicarbazones - chemical synthesis</subject><subject>Thiosemicarbazones - chemistry</subject><subject>Thiosemicarbazones - pharmacology</subject><subject>Thiosemicarbazones - therapeutic use</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1PxCAQhonR6Lr6D4zhqIeuQEtpj6bxo8kaPaxeGwp0i2lhLcWvo79cdHc9eppk5n1m4AHgBKMZRgRfcOFmz72SolX9LBEIEcp2wARTgqIkQ8kumIQeiUhK4gNw6NwzQijGJN4HB3HGWEbTdAK-Fq22TvVa8KHmn9YoeKfflYyeeKeMULDwZ-VFWZ7DwvarTr1DvuTauBHOvVnCS6mMDajQxvYcFqrrHBzbwfplC-98N-rAwAc-tm_8w8HSvNruVQew8KvBrkbrtDsCew3vnDre1Cl4vL5aFLfR_P6mLC7nESc5G6OcZQmjdY0a0cgmz9M0EzlhkmZ5QxmORZJIJCipsWyUpIyxXIZgaNSYECnjKThb7w2XX7xyY9VrJ8KLuVHWuypGNCc0RUHRFCTrqBisc4NqqtWgez58VBhVP_arYL_a2q829gN2urng6zD7g7a6QwCtA7-49YMJH_5_5zdfX5a1</recordid><startdate>20240613</startdate><enddate>20240613</enddate><creator>Li, Aili</creator><creator>Huang, Kai</creator><creator>Pan, Weiping</creator><creator>Wu, Youru</creator><creator>Liang, Yuwei</creator><creator>Zhang, ZhenLei</creator><creator>Wu, Daqi</creator><creator>Ma, Libing</creator><creator>Gou, Yi</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><orcidid>https://orcid.org/0000-0002-2900-4983</orcidid></search><sort><creationdate>20240613</creationdate><title>Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis</title><author>Li, Aili ; Huang, Kai ; Pan, Weiping ; Wu, Youru ; Liang, Yuwei ; Zhang, ZhenLei ; Wu, Daqi ; Ma, Libing ; Gou, Yi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a297t-978475bb0fcfdf99668c927d589f5713c44d0c52b1dfed57779dfdf52bb122dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>A549 Cells</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma of Lung - drug therapy</topic><topic>Adenocarcinoma of Lung - pathology</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Coordination Complexes - chemical synthesis</topic><topic>Coordination Complexes - chemistry</topic><topic>Coordination Complexes - pharmacology</topic><topic>Coordination Complexes - therapeutic use</topic><topic>Copper - chemistry</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Hemolysis - drug effects</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - pathology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Signal Transduction - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>Thiosemicarbazones - chemical synthesis</topic><topic>Thiosemicarbazones - chemistry</topic><topic>Thiosemicarbazones - pharmacology</topic><topic>Thiosemicarbazones - therapeutic use</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Aili</creatorcontrib><creatorcontrib>Huang, Kai</creatorcontrib><creatorcontrib>Pan, Weiping</creatorcontrib><creatorcontrib>Wu, Youru</creatorcontrib><creatorcontrib>Liang, Yuwei</creatorcontrib><creatorcontrib>Zhang, ZhenLei</creatorcontrib><creatorcontrib>Wu, Daqi</creatorcontrib><creatorcontrib>Ma, Libing</creatorcontrib><creatorcontrib>Gou, Yi</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>Li, Aili</au><au>Huang, Kai</au><au>Pan, Weiping</au><au>Wu, Youru</au><au>Liang, Yuwei</au><au>Zhang, ZhenLei</au><au>Wu, Daqi</au><au>Ma, Libing</au><au>Gou, Yi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-06-13</date><risdate>2024</risdate><volume>67</volume><issue>11</issue><spage>9091</spage><epage>9103</epage><pages>9091-9103</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII 2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38778566</pmid><doi>10.1021/acs.jmedchem.4c00257</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-2900-4983</orcidid></addata></record> |
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| subjects | A549 Cells Adenocarcinoma - drug therapy Adenocarcinoma - pathology Adenocarcinoma of Lung - drug therapy Adenocarcinoma of Lung - pathology Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects Coordination Complexes - chemical synthesis Coordination Complexes - chemistry Coordination Complexes - pharmacology Coordination Complexes - therapeutic use Copper - chemistry Drug Screening Assays, Antitumor Hemolysis - drug effects Humans Lung Neoplasms - drug therapy Lung Neoplasms - pathology Mice Mice, Inbred BALB C Mice, Nude Signal Transduction - drug effects Structure-Activity Relationship Thiosemicarbazones - chemical synthesis Thiosemicarbazones - chemistry Thiosemicarbazones - pharmacology Thiosemicarbazones - therapeutic use Xenograft Model Antitumor Assays |
| title | Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis |
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