Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT)
Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20−80-fold less toxic t...
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| Veröffentlicht in: | Journal of medicinal chemistry 1999-09, Vol.42 (18), p.3623-3628 |
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| container_title | Journal of medicinal chemistry |
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| creator | Leu, Yu-Ling Roffler, Steve R Chern, Ji-Wang |
| description | Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20−80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of β-glucuronidase and 4 or 12 to tumor cells resulted in a cytotoxic effect equal to that of 9-aminocamptothecin alone. Prodrugs 4 and 12 were over 80 and 4000 times more soluble than 9-aminocamptothecin in aqueous solutions at pH 4.0, respectively. Compounds 4 and 12 may be useful for prodrug monotherapy of tumors that accumulate extracellular lysosomal β-glucuronidase as well as for antibody-directed enzyme prodrug therapy (ADEPT) of cancer. |
| doi_str_mv | 10.1021/jm990124q |
| format | Article |
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Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20−80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of β-glucuronidase and 4 or 12 to tumor cells resulted in a cytotoxic effect equal to that of 9-aminocamptothecin alone. Prodrugs 4 and 12 were over 80 and 4000 times more soluble than 9-aminocamptothecin in aqueous solutions at pH 4.0, respectively. Compounds 4 and 12 may be useful for prodrug monotherapy of tumors that accumulate extracellular lysosomal β-glucuronidase as well as for antibody-directed enzyme prodrug therapy (ADEPT) of cancer.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm990124q</identifier><identifier>PMID: 10479293</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>9-aminocamptothecin ; Antibodies - pharmacology ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; camptothecin ; Camptothecin - analogs & derivatives ; Drug Design ; General aspects ; Glucuronates - chemical synthesis ; Glucuronates - pharmacology ; Glucuronidase - metabolism ; glucuronides ; Humans ; Hydrogen-Ion Concentration ; Immunotherapy - methods ; Medical sciences ; Pharmacology. Drug treatments ; Prodrugs - chemical synthesis ; Prodrugs - pharmacology ; Solubility ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 1999-09, Vol.42 (18), p.3623-3628</ispartof><rights>Copyright © 1999 American Chemical Society</rights><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a475t-1dd37f9ef84ca7a34cd3096de8aac8d902d179ed82351d67308d045fbd49208f3</citedby><cites>FETCH-LOGICAL-a475t-1dd37f9ef84ca7a34cd3096de8aac8d902d179ed82351d67308d045fbd49208f3</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/jm990124q$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm990124q$$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=1968274$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10479293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leu, Yu-Ling</creatorcontrib><creatorcontrib>Roffler, Steve R</creatorcontrib><creatorcontrib>Chern, Ji-Wang</creatorcontrib><title>Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT)</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20−80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of β-glucuronidase and 4 or 12 to tumor cells resulted in a cytotoxic effect equal to that of 9-aminocamptothecin alone. Prodrugs 4 and 12 were over 80 and 4000 times more soluble than 9-aminocamptothecin in aqueous solutions at pH 4.0, respectively. Compounds 4 and 12 may be useful for prodrug monotherapy of tumors that accumulate extracellular lysosomal β-glucuronidase as well as for antibody-directed enzyme prodrug therapy (ADEPT) of cancer.</description><subject>9-aminocamptothecin</subject><subject>Antibodies - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>camptothecin</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Drug Design</subject><subject>General aspects</subject><subject>Glucuronates - chemical synthesis</subject><subject>Glucuronates - pharmacology</subject><subject>Glucuronidase - metabolism</subject><subject>glucuronides</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Immunotherapy - methods</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - pharmacology</subject><subject>Solubility</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0c1uEzEQAGALgWgoHHgBtAdA7WHBfxuvjyEJAZFCpISfm-XY3uJ0107t3arL2_CmuN0ocOBk2fPN2J4B4DmCbxDE6O2u4RwiTK8fgBEqMMxpCelDMIIQ4xyPMTkBT2LcQQgJwuQxOEGQMo45GYHfMxPtpcuk09m6d-3PtI2Zr7LvsjUhX_u629YmW9Sd6oJ3VptsZoK9ka29MfdwKpt961Oisi6rfEgHTpmQrYLXobvMLry7iwa57-9vmbjWbr3u85kNRrVGZ3P3q2_MMWFzwGeT2Xy1OX8KHlWyjubZYT0FX9_PN9MP-fLL4uN0sswlZUWbI60Jq7ipSqokk4QqTSAfa1NKqUrNIdaIcaNLTAqkx4zAUkNaVFtNOYZlRU7B66HuPvjrzsRWNDYqU9fSGd9FgRiFJYM4wfMBquBjDKYS-2AbGXqBoLibhzjOI9kXh6LdtjH6HzkMIIGXByCjknUVUvNs_Ov4uMSMJpYPzMbW3B7DMlyJ9BVWiM1qLeDy3aeLH98-i0XyrwYvVRQ73wWXWvef9_0B1I6v5g</recordid><startdate>19990909</startdate><enddate>19990909</enddate><creator>Leu, Yu-Ling</creator><creator>Roffler, Steve R</creator><creator>Chern, Ji-Wang</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>19990909</creationdate><title>Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT)</title><author>Leu, Yu-Ling ; Roffler, Steve R ; Chern, Ji-Wang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a475t-1dd37f9ef84ca7a34cd3096de8aac8d902d179ed82351d67308d045fbd49208f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>9-aminocamptothecin</topic><topic>Antibodies - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>camptothecin</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Drug Design</topic><topic>General aspects</topic><topic>Glucuronates - chemical synthesis</topic><topic>Glucuronates - pharmacology</topic><topic>Glucuronidase - metabolism</topic><topic>glucuronides</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Immunotherapy - methods</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - pharmacology</topic><topic>Solubility</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Leu, Yu-Ling</creatorcontrib><creatorcontrib>Roffler, Steve R</creatorcontrib><creatorcontrib>Chern, Ji-Wang</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leu, Yu-Ling</au><au>Roffler, Steve R</au><au>Chern, Ji-Wang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1999-09-09</date><risdate>1999</risdate><volume>42</volume><issue>18</issue><spage>3623</spage><epage>3628</epage><pages>3623-3628</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20−80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of β-glucuronidase and 4 or 12 to tumor cells resulted in a cytotoxic effect equal to that of 9-aminocamptothecin alone. Prodrugs 4 and 12 were over 80 and 4000 times more soluble than 9-aminocamptothecin in aqueous solutions at pH 4.0, respectively. Compounds 4 and 12 may be useful for prodrug monotherapy of tumors that accumulate extracellular lysosomal β-glucuronidase as well as for antibody-directed enzyme prodrug therapy (ADEPT) of cancer.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>10479293</pmid><doi>10.1021/jm990124q</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1999-09, Vol.42 (18), p.3623-3628 |
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| subjects | 9-aminocamptothecin Antibodies - pharmacology Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Biological and medical sciences camptothecin Camptothecin - analogs & derivatives Drug Design General aspects Glucuronates - chemical synthesis Glucuronates - pharmacology Glucuronidase - metabolism glucuronides Humans Hydrogen-Ion Concentration Immunotherapy - methods Medical sciences Pharmacology. Drug treatments Prodrugs - chemical synthesis Prodrugs - pharmacology Solubility Tumor Cells, Cultured |
| title | Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT) |
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