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Potential Tumor-Selective Nitroimidazolylmethyluracil Prodrug Derivatives: Inhibitors of the Angiogenic Enzyme Thymidine Phosphorylase
Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2‘-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (...
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| Published in: | Journal of medicinal chemistry 2003-01, Vol.46 (2), p.207-209 |
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| Main Authors: | , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a476t-f9a236499aec76073dc7b5e02296247aba9b1dffb07547fb9408947376fdda913 |
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| cites | cdi_FETCH-LOGICAL-a476t-f9a236499aec76073dc7b5e02296247aba9b1dffb07547fb9408947376fdda913 |
| container_end_page | 209 |
| container_issue | 2 |
| container_start_page | 207 |
| container_title | Journal of medicinal chemistry |
| container_volume | 46 |
| creator | Cole, Christian Reigan, Philip Gbaj, Abdul Edwards, Philip N Douglas, Kenneth T Stratford, Ian J Freeman, Sally Jaffar, Mohammed |
| description | Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2‘-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2‘-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22−24 μM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed. |
| doi_str_mv | 10.1021/jm020964w |
| format | article |
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Molecular modeling suggested that 2‘-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2‘-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22−24 μM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm020964w</identifier><identifier>PMID: 12519058</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Angiogenesis Inhibitors - chemical synthesis ; Angiogenesis Inhibitors - chemistry ; Antineoplastic agents ; Binding Sites ; Biological and medical sciences ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Escherichia coli - chemistry ; General aspects ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Medical sciences ; Models, Molecular ; Nitroimidazolylmethyluracil ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Thymidine Phosphorylase - antagonists & inhibitors ; Thymidine Phosphorylase - chemistry ; Uracil - analogs & derivatives ; Uracil - chemical synthesis ; Uracil - chemistry</subject><ispartof>Journal of medicinal chemistry, 2003-01, Vol.46 (2), p.207-209</ispartof><rights>Copyright © 2003 American Chemical Society</rights><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a476t-f9a236499aec76073dc7b5e02296247aba9b1dffb07547fb9408947376fdda913</citedby><cites>FETCH-LOGICAL-a476t-f9a236499aec76073dc7b5e02296247aba9b1dffb07547fb9408947376fdda913</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14482401$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12519058$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cole, Christian</creatorcontrib><creatorcontrib>Reigan, Philip</creatorcontrib><creatorcontrib>Gbaj, Abdul</creatorcontrib><creatorcontrib>Edwards, Philip N</creatorcontrib><creatorcontrib>Douglas, Kenneth T</creatorcontrib><creatorcontrib>Stratford, Ian J</creatorcontrib><creatorcontrib>Freeman, Sally</creatorcontrib><creatorcontrib>Jaffar, Mohammed</creatorcontrib><title>Potential Tumor-Selective Nitroimidazolylmethyluracil Prodrug Derivatives: Inhibitors of the Angiogenic Enzyme Thymidine Phosphorylase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2‘-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2‘-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22−24 μM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.</description><subject>Angiogenesis Inhibitors - chemical synthesis</subject><subject>Angiogenesis Inhibitors - chemistry</subject><subject>Antineoplastic agents</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Escherichia coli - chemistry</subject><subject>General aspects</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Nitroimidazolylmethyluracil</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Thymidine Phosphorylase - antagonists & inhibitors</subject><subject>Thymidine Phosphorylase - chemistry</subject><subject>Uracil - analogs & derivatives</subject><subject>Uracil - chemical synthesis</subject><subject>Uracil - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><recordid>eNqF0TFv1DAYBmALgWgpDPwB5AUkhoDtOPGZrb0WqFTBoR4Li-U4Xy4-nPiwnUI6sfZv8kvI6U69BYnJgx-_8vt9CD2n5A0ljL5dd4QRWfKfD9AxLRjJ-Izwh-iYEMYyVrL8CD2JcU0IySnLH6MjygoqSTE7RncLn6BPVju8HDofsmtwYJK9AfzJpuBtZ2t9693oOkjt6IagjXV4EXwdhhU-h2Bv9JbHd39-3-HLvrWVTT5E7BucWsCn_cr6FfTW4Iv-duwAL9txCrU94EXr46b1YXQ6wlP0qNEuwrP9eYK-vr9Yzj9mV58_XM5PrzLNRZmyRmqWl1xKDUaUROS1EVUBU1NZMi50pWVF66apiCi4aCrJyUxykYuyqWstaX6CXu1yN8H_GCAm1dlowDndgx-iEkwWdHr0X0glY4zKLXy9gyb4GAM0ahNsp8OoKFHbBan7BU32xT50qDqoD3K_kQm83AMdjXZN0L2x8eA4nzFOtjWynbMxwa_7ex2-q3JqW6jl4lqdzb-U39jZuWKHXG2iWvsh9NOQ__HBv9kft1g</recordid><startdate>20030116</startdate><enddate>20030116</enddate><creator>Cole, Christian</creator><creator>Reigan, Philip</creator><creator>Gbaj, Abdul</creator><creator>Edwards, Philip N</creator><creator>Douglas, Kenneth T</creator><creator>Stratford, Ian J</creator><creator>Freeman, Sally</creator><creator>Jaffar, Mohammed</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>7TM</scope><scope>7X8</scope></search><sort><creationdate>20030116</creationdate><title>Potential Tumor-Selective Nitroimidazolylmethyluracil Prodrug Derivatives: Inhibitors of the Angiogenic Enzyme Thymidine Phosphorylase</title><author>Cole, Christian ; Reigan, Philip ; Gbaj, Abdul ; Edwards, Philip N ; Douglas, Kenneth T ; Stratford, Ian J ; Freeman, Sally ; Jaffar, Mohammed</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a476t-f9a236499aec76073dc7b5e02296247aba9b1dffb07547fb9408947376fdda913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Angiogenesis Inhibitors - chemical synthesis</topic><topic>Angiogenesis Inhibitors - chemistry</topic><topic>Antineoplastic agents</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Escherichia coli - chemistry</topic><topic>General aspects</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Nitroimidazolylmethyluracil</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Thymidine Phosphorylase - antagonists & inhibitors</topic><topic>Thymidine Phosphorylase - chemistry</topic><topic>Uracil - analogs & derivatives</topic><topic>Uracil - chemical synthesis</topic><topic>Uracil - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cole, Christian</creatorcontrib><creatorcontrib>Reigan, Philip</creatorcontrib><creatorcontrib>Gbaj, Abdul</creatorcontrib><creatorcontrib>Edwards, Philip N</creatorcontrib><creatorcontrib>Douglas, Kenneth T</creatorcontrib><creatorcontrib>Stratford, Ian J</creatorcontrib><creatorcontrib>Freeman, Sally</creatorcontrib><creatorcontrib>Jaffar, Mohammed</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>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cole, Christian</au><au>Reigan, Philip</au><au>Gbaj, Abdul</au><au>Edwards, Philip N</au><au>Douglas, Kenneth T</au><au>Stratford, Ian J</au><au>Freeman, Sally</au><au>Jaffar, Mohammed</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potential Tumor-Selective Nitroimidazolylmethyluracil Prodrug Derivatives: Inhibitors of the Angiogenic Enzyme Thymidine Phosphorylase</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2003-01-16</date><risdate>2003</risdate><volume>46</volume><issue>2</issue><spage>207</spage><epage>209</epage><pages>207-209</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2‘-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2‘-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22−24 μM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>12519058</pmid><doi>10.1021/jm020964w</doi><tpages>3</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2003-01, Vol.46 (2), p.207-209 |
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| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Angiogenesis Inhibitors - chemical synthesis Angiogenesis Inhibitors - chemistry Antineoplastic agents Binding Sites Biological and medical sciences Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Escherichia coli - chemistry General aspects Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Medical sciences Models, Molecular Nitroimidazolylmethyluracil Pharmacology. Drug treatments Structure-Activity Relationship Thymidine Phosphorylase - antagonists & inhibitors Thymidine Phosphorylase - chemistry Uracil - analogs & derivatives Uracil - chemical synthesis Uracil - chemistry |
| title | Potential Tumor-Selective Nitroimidazolylmethyluracil Prodrug Derivatives: Inhibitors of the Angiogenic Enzyme Thymidine Phosphorylase |
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