Electron-Deficient DNA Intercalating Agents as Antitumor Drugs: Aza Analogs of the Experimental Clinical Agent N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide
A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement a...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-03, Vol.37 (5), p.593-597 |
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| container_issue | 5 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Chen, Qingping Deady, Leslie W Baguley, Bruce C Denny, William A |
| description | A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake. |
| doi_str_mv | 10.1021/jm00031a008 |
| format | Article |
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These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00031a008</identifier><identifier>PMID: 8126699</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acridines - chemistry ; Acridines - metabolism ; Acridines - therapeutic use ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - therapeutic use ; Chemistry ; DNA - metabolism ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings ; Intercalating Agents - chemical synthesis ; Intercalating Agents - metabolism ; Intercalating Agents - therapeutic use ; Leukemia P388 - drug therapy ; Mice ; Molecular Structure ; Naphthyridines - chemical synthesis ; Naphthyridines - metabolism ; Naphthyridines - therapeutic use ; Neoplasm Transplantation ; Organic chemistry ; Preparations and properties ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1994-03, Vol.37 (5), p.593-597</ispartof><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-6ceff43c85d0cbcd3d437f8f068a6b8453af7fc50fd1369c1e662d7e5dfd5ce13</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00031a008$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00031a008$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3968027$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8126699$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Qingping</creatorcontrib><creatorcontrib>Deady, Leslie W</creatorcontrib><creatorcontrib>Baguley, Bruce C</creatorcontrib><creatorcontrib>Denny, William A</creatorcontrib><title>Electron-Deficient DNA Intercalating Agents as Antitumor Drugs: Aza Analogs of the Experimental Clinical Agent N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.</description><subject>Acridines - chemistry</subject><subject>Acridines - metabolism</subject><subject>Acridines - therapeutic use</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Chemistry</subject><subject>DNA - metabolism</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</subject><subject>Intercalating Agents - chemical synthesis</subject><subject>Intercalating Agents - metabolism</subject><subject>Intercalating Agents - therapeutic use</subject><subject>Leukemia P388 - drug therapy</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Naphthyridines - chemical synthesis</subject><subject>Naphthyridines - metabolism</subject><subject>Naphthyridines - therapeutic use</subject><subject>Neoplasm Transplantation</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUuLFDEUhQtRxnZ05VrIQnwg0TyqUlXuyu5WB4ZRsH2ASEjn0ZOeqqRNUtDjn_GvGqeaxoWrG-757uHmnqJ4iNFLjAh-tR0QQhQLhJpbxQxXBMGyQeXtYoYQIZAwQu8W92Lc3mCEnhQnDSaMte2s-L3stUzBO7jQxkqrXQKLiw6cuaSDFL1I1m1At8n9CEQEnUs2jYMPYBHGTXwNul8iN0XvNxF4A9KlBsv9Tgc75BHRg3lvnc1Gkwe4gN8JfLbIarq87sVgnX9-8_whZLDKOg1LKEVY-30Wlb5f3DGij_rBoZ4Wn98uV_P38PzDu7N5dw5FWbYJMqmNKalsKoXkWiqqSlqbxiDWCLZuyooKUxtZIaMwZa3EmjGial0poyqpMT0tnky-u-B_jjomPtgodd8Lp_0Yec1oQ1lJM_hiAmXwMQZt-C7_VYRrjhH_Gwf_J45MPzrYjutBqyN7uH_WHx90EfORTBBO2njEaMsaROqMwQmzMen9URbhirOa1hVfffzEv7z5uprX32q-yvzTiRcy8q0fQw4o_nfBPxoGsBE</recordid><startdate>19940301</startdate><enddate>19940301</enddate><creator>Chen, Qingping</creator><creator>Deady, Leslie W</creator><creator>Baguley, Bruce C</creator><creator>Denny, William A</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><scope>7X8</scope></search><sort><creationdate>19940301</creationdate><title>Electron-Deficient DNA Intercalating Agents as Antitumor Drugs: Aza Analogs of the Experimental Clinical Agent N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide</title><author>Chen, Qingping ; Deady, Leslie W ; Baguley, Bruce C ; Denny, William A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-6ceff43c85d0cbcd3d437f8f068a6b8453af7fc50fd1369c1e662d7e5dfd5ce13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Acridines - chemistry</topic><topic>Acridines - metabolism</topic><topic>Acridines - therapeutic use</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Chemistry</topic><topic>DNA - metabolism</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</topic><topic>Intercalating Agents - chemical synthesis</topic><topic>Intercalating Agents - metabolism</topic><topic>Intercalating Agents - therapeutic use</topic><topic>Leukemia P388 - drug therapy</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Naphthyridines - chemical synthesis</topic><topic>Naphthyridines - metabolism</topic><topic>Naphthyridines - therapeutic use</topic><topic>Neoplasm Transplantation</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Qingping</creatorcontrib><creatorcontrib>Deady, Leslie W</creatorcontrib><creatorcontrib>Baguley, Bruce C</creatorcontrib><creatorcontrib>Denny, William A</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><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Qingping</au><au>Deady, Leslie W</au><au>Baguley, Bruce C</au><au>Denny, William A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Electron-Deficient DNA Intercalating Agents as Antitumor Drugs: Aza Analogs of the Experimental Clinical Agent N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-03-01</date><risdate>1994</risdate><volume>37</volume><issue>5</issue><spage>593</spage><epage>597</epage><pages>593-597</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8126699</pmid><doi>10.1021/jm00031a008</doi><tpages>5</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1994-03, Vol.37 (5), p.593-597 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Acridines - chemistry Acridines - metabolism Acridines - therapeutic use Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - metabolism Antineoplastic Agents - therapeutic use Chemistry DNA - metabolism Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Intercalating Agents - chemical synthesis Intercalating Agents - metabolism Intercalating Agents - therapeutic use Leukemia P388 - drug therapy Mice Molecular Structure Naphthyridines - chemical synthesis Naphthyridines - metabolism Naphthyridines - therapeutic use Neoplasm Transplantation Organic chemistry Preparations and properties Structure-Activity Relationship |
| title | Electron-Deficient DNA Intercalating Agents as Antitumor Drugs: Aza Analogs of the Experimental Clinical Agent N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide |
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