Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects
Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of...
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| Veröffentlicht in: | Inorganic chemistry 2022-03, Vol.61 (12), p.4919-4937 |
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| creator | Del Bello, Fabio Pellei, Maura Bagnarelli, Luca Santini, Carlo Giorgioni, Gianfabio Piergentili, Alessandro Quaglia, Wilma Battocchio, Chiara Iucci, Giovanna Schiesaro, Irene Meneghini, Carlo Venditti, Iole Ramanan, Nitya De Franco, Michele Sgarbossa, Paolo Marzano, Cristina Gandin, Valentina |
| description | Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death. |
| doi_str_mv | 10.1021/acs.inorgchem.1c03658 |
| format | Article |
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Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.</description><identifier>ISSN: 0020-1669</identifier><identifier>EISSN: 1520-510X</identifier><identifier>DOI: 10.1021/acs.inorgchem.1c03658</identifier><identifier>PMID: 35285628</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Coordination Complexes - chemistry ; Coordination Complexes - pharmacology ; Copper - chemistry ; Copper - pharmacology ; Crystallography, X-Ray ; Humans ; Indazoles ; Ligands ; Molecular Structure</subject><ispartof>Inorganic chemistry, 2022-03, Vol.61 (12), p.4919-4937</ispartof><rights>2022 The Authors. Published by American Chemical Society</rights><rights>2022 The Authors. 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Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Coordination Complexes - chemistry</subject><subject>Coordination Complexes - pharmacology</subject><subject>Copper - chemistry</subject><subject>Copper - pharmacology</subject><subject>Crystallography, X-Ray</subject><subject>Humans</subject><subject>Indazoles</subject><subject>Ligands</subject><subject>Molecular Structure</subject><issn>0020-1669</issn><issn>1520-510X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU2PFCEUJEbjjqs_QcNxPcwITUPDxWS3XXWTSTRxD94IzUcvk24YgTbuv5fJjBM9eXqV96rqwSsAXmO0wajB75TOGx9iGvWDnTdYI8IofwJWmDZoTTH6_hSsEKoYMyYuwIucdwghQVr2HFwQ2nDKGr4CuV-u7t5CFQw8oAr7OO8n-8tmeKOyNTAGuI3BGzX7YNd9DLtlVKUOtn6ssgw_2OzHUBslwq8pzrFY-O0x2DT6XLyG16H4sswxwVvnrC75JXjm1JTtq1O9BPcfb-_7z-vtl093_fV2rVpKyuETghirRNt1RjesU5wZilUraCuM7pjpBk0H4ThWWnAiHHaOMjdwM2DWkkvw_mi7X4bZGm1DSWqS--RnlR5lVF7-Own-QY7xp-SinrIT1eDqZJDij8XmImeftZ0mFWxcsmwY4aLFCJFKpUeqTjHnZN15DUbykJeseclzXvKUV9W9-fuNZ9WfgCoBHwkH_S4uKdSL_cf0N1jAp_I</recordid><startdate>20220328</startdate><enddate>20220328</enddate><creator>Del Bello, Fabio</creator><creator>Pellei, Maura</creator><creator>Bagnarelli, Luca</creator><creator>Santini, Carlo</creator><creator>Giorgioni, Gianfabio</creator><creator>Piergentili, Alessandro</creator><creator>Quaglia, Wilma</creator><creator>Battocchio, Chiara</creator><creator>Iucci, Giovanna</creator><creator>Schiesaro, Irene</creator><creator>Meneghini, Carlo</creator><creator>Venditti, Iole</creator><creator>Ramanan, Nitya</creator><creator>De Franco, Michele</creator><creator>Sgarbossa, Paolo</creator><creator>Marzano, Cristina</creator><creator>Gandin, Valentina</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6135-6826</orcidid><orcidid>https://orcid.org/0000-0003-4846-8422</orcidid><orcidid>https://orcid.org/0000-0003-4590-0865</orcidid><orcidid>https://orcid.org/0000-0002-3942-1713</orcidid><orcidid>https://orcid.org/0000-0001-5020-1730</orcidid><orcidid>https://orcid.org/0000-0001-6538-6029</orcidid><orcidid>https://orcid.org/0000-0002-0938-953X</orcidid><orcidid>https://orcid.org/0000-0002-6478-3759</orcidid><orcidid>https://orcid.org/0000-0002-7708-0200</orcidid><orcidid>https://orcid.org/0000-0002-9576-6580</orcidid><orcidid>https://orcid.org/0000-0002-9306-573X</orcidid></search><sort><creationdate>20220328</creationdate><title>Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects</title><author>Del Bello, Fabio ; 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Chem</addtitle><date>2022-03-28</date><risdate>2022</risdate><volume>61</volume><issue>12</issue><spage>4919</spage><epage>4937</epage><pages>4919-4937</pages><issn>0020-1669</issn><eissn>1520-510X</eissn><abstract>Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>35285628</pmid><doi>10.1021/acs.inorgchem.1c03658</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0001-6135-6826</orcidid><orcidid>https://orcid.org/0000-0003-4846-8422</orcidid><orcidid>https://orcid.org/0000-0003-4590-0865</orcidid><orcidid>https://orcid.org/0000-0002-3942-1713</orcidid><orcidid>https://orcid.org/0000-0001-5020-1730</orcidid><orcidid>https://orcid.org/0000-0001-6538-6029</orcidid><orcidid>https://orcid.org/0000-0002-0938-953X</orcidid><orcidid>https://orcid.org/0000-0002-6478-3759</orcidid><orcidid>https://orcid.org/0000-0002-7708-0200</orcidid><orcidid>https://orcid.org/0000-0002-9576-6580</orcidid><orcidid>https://orcid.org/0000-0002-9306-573X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Coordination Complexes - chemistry Coordination Complexes - pharmacology Copper - chemistry Copper - pharmacology Crystallography, X-Ray Humans Indazoles Ligands Molecular Structure |
| title | Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects |
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