Alkyl Substituted 2′-Benzoylpyridine Thiosemicarbazone Chelators with Potent and Selective Anti-Neoplastic Activity: Novel Ligands that Limit Methemoglobin Formation
Thiosemicarbazone chelators, including the 2′-benzoylpyridine thiosemicarbazones (BpT) class, show marked potential as anticancer agents. Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects assoc...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-01, Vol.56 (1), p.357-370 |
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| creator | Stefani, Christian Jansson, Patric J Gutierrez, Elaine Bernhardt, Paul V Richardson, Des R Kalinowski, Danuta S |
| description | Thiosemicarbazone chelators, including the 2′-benzoylpyridine thiosemicarbazones (BpT) class, show marked potential as anticancer agents. Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects associated with 3-AP administration include methemoglobinemia. Considering this problem, novel BpT analogues were designed bearing hydrophobic, electron-donating substituents at the para position of the phenyl group (RBpT). Their FeIII/II redox potentials were all within the range accessible to cellular oxidants and reductants, suggesting they can redox cycle. These RBpT ligands exhibited potent and selective antiproliferative activity, which was comparable or exceeded their BpT counterparts. Major findings include that methemoglobin formation mediated by the lipophilic t-BuBpT series was significantly (p < 0.05–0.001) decreased in comparison to 3-AP in intact red blood cells and were generally comparable to the control. These data indicate the t-BuBpT ligands may minimize methemoglobinemia, which is a marked advantage over 3-AP and other potent thiosemicarbazones. |
| doi_str_mv | 10.1021/jm301691s |
| format | Article |
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Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects associated with 3-AP administration include methemoglobinemia. Considering this problem, novel BpT analogues were designed bearing hydrophobic, electron-donating substituents at the para position of the phenyl group (RBpT). Their FeIII/II redox potentials were all within the range accessible to cellular oxidants and reductants, suggesting they can redox cycle. These RBpT ligands exhibited potent and selective antiproliferative activity, which was comparable or exceeded their BpT counterparts. Major findings include that methemoglobin formation mediated by the lipophilic t-BuBpT series was significantly (p < 0.05–0.001) decreased in comparison to 3-AP in intact red blood cells and were generally comparable to the control. These data indicate the t-BuBpT ligands may minimize methemoglobinemia, which is a marked advantage over 3-AP and other potent thiosemicarbazones.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm301691s</identifier><identifier>PMID: 23276209</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Ascorbic Acid - chemistry ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Coordination Complexes - chemical synthesis ; Coordination Complexes - chemistry ; Coordination Complexes - pharmacology ; Crystallography, X-Ray ; Drug Screening Assays, Antitumor ; Ferric Compounds - chemical synthesis ; Ferric Compounds - chemistry ; Ferrous Compounds - chemical synthesis ; Ferrous Compounds - chemistry ; Humans ; Iron Chelating Agents - chemical synthesis ; Iron Chelating Agents - chemistry ; Iron Chelating Agents - pharmacology ; Ligands ; Methemoglobin - biosynthesis ; Molecular Structure ; Oxidation-Reduction ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Structure-Activity Relationship ; Thiosemicarbazones - chemical synthesis ; Thiosemicarbazones - chemistry ; Thiosemicarbazones - pharmacology ; Transferrin - metabolism</subject><ispartof>Journal of medicinal chemistry, 2013-01, Vol.56 (1), p.357-370</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-156cb6dfb6480f0c28ec86e7e29f21b6d9f2658dd950d031246a0dacc04677963</citedby><cites>FETCH-LOGICAL-a315t-156cb6dfb6480f0c28ec86e7e29f21b6d9f2658dd950d031246a0dacc04677963</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/jm301691s$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm301691s$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2764,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23276209$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stefani, Christian</creatorcontrib><creatorcontrib>Jansson, Patric J</creatorcontrib><creatorcontrib>Gutierrez, Elaine</creatorcontrib><creatorcontrib>Bernhardt, Paul V</creatorcontrib><creatorcontrib>Richardson, Des R</creatorcontrib><creatorcontrib>Kalinowski, Danuta S</creatorcontrib><title>Alkyl Substituted 2′-Benzoylpyridine Thiosemicarbazone Chelators with Potent and Selective Anti-Neoplastic Activity: Novel Ligands that Limit Methemoglobin Formation</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Thiosemicarbazone chelators, including the 2′-benzoylpyridine thiosemicarbazones (BpT) class, show marked potential as anticancer agents. Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects associated with 3-AP administration include methemoglobinemia. Considering this problem, novel BpT analogues were designed bearing hydrophobic, electron-donating substituents at the para position of the phenyl group (RBpT). Their FeIII/II redox potentials were all within the range accessible to cellular oxidants and reductants, suggesting they can redox cycle. These RBpT ligands exhibited potent and selective antiproliferative activity, which was comparable or exceeded their BpT counterparts. Major findings include that methemoglobin formation mediated by the lipophilic t-BuBpT series was significantly (p < 0.05–0.001) decreased in comparison to 3-AP in intact red blood cells and were generally comparable to the control. These data indicate the t-BuBpT ligands may minimize methemoglobinemia, which is a marked advantage over 3-AP and other potent thiosemicarbazones.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Ascorbic Acid - chemistry</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>Crystallography, X-Ray</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Ferric Compounds - chemical synthesis</subject><subject>Ferric Compounds - chemistry</subject><subject>Ferrous Compounds - chemical synthesis</subject><subject>Ferrous Compounds - chemistry</subject><subject>Humans</subject><subject>Iron Chelating Agents - chemical synthesis</subject><subject>Iron Chelating Agents - chemistry</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Ligands</subject><subject>Methemoglobin - biosynthesis</subject><subject>Molecular Structure</subject><subject>Oxidation-Reduction</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Thiosemicarbazones - chemical synthesis</subject><subject>Thiosemicarbazones - chemistry</subject><subject>Thiosemicarbazones - pharmacology</subject><subject>Transferrin - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc9u1DAQxi0EokvhwAsgX5DKIeA_GyfhtqwoVFoKUss5cuxJ48WxF9tplZ54G-48Ek9Sr7b0xGk0M7_5pPk-hF5S8pYSRt9tR06oaGh8hBa0ZKRY1mT5GC0IYaxggvEj9CzGLSGEU8afoiPGWSUYaRbo98r-mC2-mLqYTJoSaMz-_vpTfAB362e7m4PRxgG-HIyPMBolQydvfZ6sB7Ay-RDxjUkD_uYTuISl0_gCLKhkrgGvXDLFOfidlVle4dV-bNL8Hp_7a7B4Y67yQcRpkCk3o0n4C6QBRn9lfWccPvVhlMl49xw96aWN8OK-HqPvpx8v15-LzddPZ-vVppCclqmgpVCd0H0nsgU9UawGVQuogDU9o3mTiyhrrZuS6L0bSyGJlkqRpaiqRvBjdHLQ3QX_c4KY2tFEBdZKB36KLWUV53VFqyqjbw6oCj7GAH27C2aUYW4pafe5tA-5ZPbVvezUjaAfyH9BZOD1AZAqtls_BZe__I_QHbV9mOQ</recordid><startdate>20130110</startdate><enddate>20130110</enddate><creator>Stefani, Christian</creator><creator>Jansson, Patric J</creator><creator>Gutierrez, Elaine</creator><creator>Bernhardt, Paul V</creator><creator>Richardson, Des R</creator><creator>Kalinowski, Danuta S</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>20130110</creationdate><title>Alkyl Substituted 2′-Benzoylpyridine Thiosemicarbazone Chelators with Potent and Selective Anti-Neoplastic Activity: Novel Ligands that Limit Methemoglobin Formation</title><author>Stefani, Christian ; Jansson, Patric J ; Gutierrez, Elaine ; Bernhardt, Paul V ; Richardson, Des R ; Kalinowski, Danuta S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-156cb6dfb6480f0c28ec86e7e29f21b6d9f2658dd950d031246a0dacc04677963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Ascorbic Acid - chemistry</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>Crystallography, X-Ray</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Ferric Compounds - chemical synthesis</topic><topic>Ferric Compounds - chemistry</topic><topic>Ferrous Compounds - chemical synthesis</topic><topic>Ferrous Compounds - chemistry</topic><topic>Humans</topic><topic>Iron Chelating Agents - chemical synthesis</topic><topic>Iron Chelating Agents - chemistry</topic><topic>Iron Chelating Agents - pharmacology</topic><topic>Ligands</topic><topic>Methemoglobin - biosynthesis</topic><topic>Molecular Structure</topic><topic>Oxidation-Reduction</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Thiosemicarbazones - chemical synthesis</topic><topic>Thiosemicarbazones - chemistry</topic><topic>Thiosemicarbazones - pharmacology</topic><topic>Transferrin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stefani, Christian</creatorcontrib><creatorcontrib>Jansson, Patric J</creatorcontrib><creatorcontrib>Gutierrez, Elaine</creatorcontrib><creatorcontrib>Bernhardt, Paul V</creatorcontrib><creatorcontrib>Richardson, Des R</creatorcontrib><creatorcontrib>Kalinowski, Danuta S</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>Stefani, Christian</au><au>Jansson, Patric J</au><au>Gutierrez, Elaine</au><au>Bernhardt, Paul V</au><au>Richardson, Des R</au><au>Kalinowski, Danuta S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alkyl Substituted 2′-Benzoylpyridine Thiosemicarbazone Chelators with Potent and Selective Anti-Neoplastic Activity: Novel Ligands that Limit Methemoglobin Formation</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-01-10</date><risdate>2013</risdate><volume>56</volume><issue>1</issue><spage>357</spage><epage>370</epage><pages>357-370</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Thiosemicarbazone chelators, including the 2′-benzoylpyridine thiosemicarbazones (BpT) class, show marked potential as anticancer agents. Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects associated with 3-AP administration include methemoglobinemia. Considering this problem, novel BpT analogues were designed bearing hydrophobic, electron-donating substituents at the para position of the phenyl group (RBpT). Their FeIII/II redox potentials were all within the range accessible to cellular oxidants and reductants, suggesting they can redox cycle. These RBpT ligands exhibited potent and selective antiproliferative activity, which was comparable or exceeded their BpT counterparts. Major findings include that methemoglobin formation mediated by the lipophilic t-BuBpT series was significantly (p < 0.05–0.001) decreased in comparison to 3-AP in intact red blood cells and were generally comparable to the control. These data indicate the t-BuBpT ligands may minimize methemoglobinemia, which is a marked advantage over 3-AP and other potent thiosemicarbazones.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23276209</pmid><doi>10.1021/jm301691s</doi><tpages>14</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Ascorbic Acid - chemistry Cell Line, Tumor Cell Proliferation - drug effects Coordination Complexes - chemical synthesis Coordination Complexes - chemistry Coordination Complexes - pharmacology Crystallography, X-Ray Drug Screening Assays, Antitumor Ferric Compounds - chemical synthesis Ferric Compounds - chemistry Ferrous Compounds - chemical synthesis Ferrous Compounds - chemistry Humans Iron Chelating Agents - chemical synthesis Iron Chelating Agents - chemistry Iron Chelating Agents - pharmacology Ligands Methemoglobin - biosynthesis Molecular Structure Oxidation-Reduction Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Structure-Activity Relationship Thiosemicarbazones - chemical synthesis Thiosemicarbazones - chemistry Thiosemicarbazones - pharmacology Transferrin - metabolism |
| title | Alkyl Substituted 2′-Benzoylpyridine Thiosemicarbazone Chelators with Potent and Selective Anti-Neoplastic Activity: Novel Ligands that Limit Methemoglobin Formation |
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