Synthesis of a Prodrug Designed To Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept
The synthesis of a novel acetoxymethyltriazene designed to be a prodrug of multiple inhibitors of the epidermal growth factor receptor (EGFR) and a methyldiazonium species is described. Studies with each of the expected metabolites demonstrated significant EGFR tyrosine kinase inhibitory activities...
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| Veröffentlicht in: | Journal of medicinal chemistry 2003-12, Vol.46 (25), p.5546-5551 |
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| container_end_page | 5551 |
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| container_issue | 25 |
| container_start_page | 5546 |
| container_title | Journal of medicinal chemistry |
| container_volume | 46 |
| creator | Banerjee, Ranjita Rachid, Zakaria McNamee, James Jean-Claude, Bertrand J |
| description | The synthesis of a novel acetoxymethyltriazene designed to be a prodrug of multiple inhibitors of the epidermal growth factor receptor (EGFR) and a methyldiazonium species is described. Studies with each of the expected metabolites demonstrated significant EGFR tyrosine kinase inhibitory activities and the released methyldiazonium was trapped with p-nitrobenzylpyridine. Their ability to damage genomic DNA in whole cells was demonstrated by using the single cell microelectrophoresis (comet) assay. The results suggest that this approach may well represent a novel drug combination strategy involving single molecules masking multiple bioactive agents. |
| doi_str_mv | 10.1021/jm030423m |
| format | Article |
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Studies with each of the expected metabolites demonstrated significant EGFR tyrosine kinase inhibitory activities and the released methyldiazonium was trapped with p-nitrobenzylpyridine. Their ability to damage genomic DNA in whole cells was demonstrated by using the single cell microelectrophoresis (comet) assay. The results suggest that this approach may well represent a novel drug combination strategy involving single molecules masking multiple bioactive agents.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm030423m</identifier><identifier>PMID: 14640561</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents, Alkylating - chemical synthesis ; Antineoplastic Agents, Alkylating - metabolism ; Antineoplastic Agents, Alkylating - pharmacology ; Biological and medical sciences ; Cell Line ; Comet Assay ; Diazonium Compounds - metabolism ; DNA Damage ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - metabolism ; General aspects ; Humans ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Prodrugs - chemical synthesis ; Prodrugs - metabolism ; Prodrugs - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Structure-Activity Relationship ; Triazenes - chemical synthesis ; Triazenes - metabolism ; Triazenes - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2003-12, Vol.46 (25), p.5546-5551</ispartof><rights>Copyright © 2003 American Chemical Society</rights><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a379t-aaf6c480ad302751e7a71c4ffefe5a53287b37027da3a017e9bd8c4de224dc7f3</citedby><cites>FETCH-LOGICAL-a379t-aaf6c480ad302751e7a71c4ffefe5a53287b37027da3a017e9bd8c4de224dc7f3</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/jm030423m$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm030423m$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15331385$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14640561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Banerjee, Ranjita</creatorcontrib><creatorcontrib>Rachid, Zakaria</creatorcontrib><creatorcontrib>McNamee, James</creatorcontrib><creatorcontrib>Jean-Claude, Bertrand J</creatorcontrib><title>Synthesis of a Prodrug Designed To Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis of a novel acetoxymethyltriazene designed to be a prodrug of multiple inhibitors of the epidermal growth factor receptor (EGFR) and a methyldiazonium species is described. Studies with each of the expected metabolites demonstrated significant EGFR tyrosine kinase inhibitory activities and the released methyldiazonium was trapped with p-nitrobenzylpyridine. Their ability to damage genomic DNA in whole cells was demonstrated by using the single cell microelectrophoresis (comet) assay. The results suggest that this approach may well represent a novel drug combination strategy involving single molecules masking multiple bioactive agents.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Alkylating - chemical synthesis</subject><subject>Antineoplastic Agents, Alkylating - metabolism</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Comet Assay</subject><subject>Diazonium Compounds - metabolism</subject><subject>DNA Damage</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - metabolism</subject><subject>Prodrugs - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Triazenes - chemical synthesis</subject><subject>Triazenes - metabolism</subject><subject>Triazenes - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1u1DAUhS0EokNhwQsgb1iwCPgniTPspkNbKlqoaFhHd5ybjKeJE9kJ7ezY8jo8Ek-C0xl1NiyufOXznaOrQ8hrzt5zJviHTcski4Vsn5AZTwSL4ozFT8mMMSEikQp5RF54v2GMSS7kc3LE4zRmScpn5M_N1g5r9MbTrqJAr11XurGmn8JXbbGkeUe_Y4PgkV6NzWD6BumFXZuVGTr3YAp2etqbEl0LDT133d2wpmeggx6sGvtpybeu88Yi_WLslAW2DEMXze22gcHYmi5qtMPHv79-0wX92v3EhuZjOznB1fhALDs7pb0kzypoPL7av8fkx9lpvvwcXX47v1guLiOQaj5EAFWqQxFQSiZUwlGB4jquKqwwgUSKTK2kClIJEhhXOF-VmY5LFCIutarkMXm3y9XhdO-wKnpnWnDbgrNi6r147D2wb3ZsP65aLA_kvugAvN0D4DU0lQOrjT9wiZRcZkngoh1n_ID3jzq42yJVUiVFfn1TnFxlJ3MxT4r5IRe0Lzbd6Gyo5D8H_gOSV6ke</recordid><startdate>20031204</startdate><enddate>20031204</enddate><creator>Banerjee, Ranjita</creator><creator>Rachid, Zakaria</creator><creator>McNamee, James</creator><creator>Jean-Claude, Bertrand J</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20031204</creationdate><title>Synthesis of a Prodrug Designed To Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept</title><author>Banerjee, Ranjita ; Rachid, Zakaria ; McNamee, James ; Jean-Claude, Bertrand J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a379t-aaf6c480ad302751e7a71c4ffefe5a53287b37027da3a017e9bd8c4de224dc7f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Alkylating - chemical synthesis</topic><topic>Antineoplastic Agents, Alkylating - metabolism</topic><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Comet Assay</topic><topic>Diazonium Compounds - metabolism</topic><topic>DNA Damage</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>General aspects</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - metabolism</topic><topic>Prodrugs - pharmacology</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Triazenes - chemical synthesis</topic><topic>Triazenes - metabolism</topic><topic>Triazenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Banerjee, Ranjita</creatorcontrib><creatorcontrib>Rachid, Zakaria</creatorcontrib><creatorcontrib>McNamee, James</creatorcontrib><creatorcontrib>Jean-Claude, Bertrand J</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Banerjee, Ranjita</au><au>Rachid, Zakaria</au><au>McNamee, James</au><au>Jean-Claude, Bertrand J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of a Prodrug Designed To Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2003-12-04</date><risdate>2003</risdate><volume>46</volume><issue>25</issue><spage>5546</spage><epage>5551</epage><pages>5546-5551</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis of a novel acetoxymethyltriazene designed to be a prodrug of multiple inhibitors of the epidermal growth factor receptor (EGFR) and a methyldiazonium species is described. Studies with each of the expected metabolites demonstrated significant EGFR tyrosine kinase inhibitory activities and the released methyldiazonium was trapped with p-nitrobenzylpyridine. Their ability to damage genomic DNA in whole cells was demonstrated by using the single cell microelectrophoresis (comet) assay. The results suggest that this approach may well represent a novel drug combination strategy involving single molecules masking multiple bioactive agents.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>14640561</pmid><doi>10.1021/jm030423m</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2003-12, Vol.46 (25), p.5546-5551 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Publications |
| subjects | Animals Antineoplastic agents Antineoplastic Agents, Alkylating - chemical synthesis Antineoplastic Agents, Alkylating - metabolism Antineoplastic Agents, Alkylating - pharmacology Biological and medical sciences Cell Line Comet Assay Diazonium Compounds - metabolism DNA Damage Drug Screening Assays, Antitumor Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - metabolism General aspects Humans Medical sciences Mice Pharmacology. Drug treatments Prodrugs - chemical synthesis Prodrugs - metabolism Prodrugs - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Structure-Activity Relationship Triazenes - chemical synthesis Triazenes - metabolism Triazenes - pharmacology |
| title | Synthesis of a Prodrug Designed To Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept |
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