Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents
Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP Sc, which is a misfolded isoform of the normal cellular prion protein PrP C. Using virtual high-throughput screening we have selected structures analogous to acridine, 2...
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| Veröffentlicht in: | European journal of medicinal chemistry 2006-10, Vol.41 (10), p.1124-1143 |
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| container_title | European journal of medicinal chemistry |
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| creator | Cope, H. Mutter, R. Heal, W. Pascoe, C. Brown, P. Pratt, S. Chen, B. |
| description | Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP
Sc, which is a misfolded isoform of the normal cellular prion protein PrP
C. Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP
C and the suppression of PrP
Sc accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC
50s in the nanomolar range. |
| doi_str_mv | 10.1016/j.ejmech.2006.05.002 |
| format | Article |
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Sc, which is a misfolded isoform of the normal cellular prion protein PrP
C. Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP
C and the suppression of PrP
Sc accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC
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Sc, which is a misfolded isoform of the normal cellular prion protein PrP
C. Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP
C and the suppression of PrP
Sc accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC
50s in the nanomolar range.</description><subject>Acridine</subject><subject>Acridines - chemical synthesis</subject><subject>Acridines - chemistry</subject><subject>Acridines - pharmacology</subject><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Miscellaneous</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Prion protein</subject><subject>Prions - antagonists & inhibitors</subject><subject>Quinaldines - chemical synthesis</subject><subject>Quinaldines - chemistry</subject><subject>Quinaldines - pharmacology</subject><subject>Quinazoline</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - chemistry</subject><subject>Quinazolines - pharmacology</subject><subject>Quinoline</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>TSE</subject><subject>vCJD</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kNGK1DAUhoMo7rj6BiK90attPUmaJr0RlsVVYUFw9TqkyelOhjadSVphfJp9ln0ys3Rk77xJ4Jzv_zl8hLylUFGgzcddhbsR7bZiAE0FogJgz8iGykaVnIn6OdkAY7wUjNdn5FVKOwAQDcBLckYbqfKu2ZDD7THMW0w-FSa4h_vbyx9Fmhd3LKb-4d7Y6J0PeFGwcsR5exwOiw_TkEcrzsr9FsM6Nn_-Lcww3S2YG1OuCLMv99FPoTB3GOb0mrzozZDwzek_J7-uP_-8-lrefP_y7eryprS8hbm0tlaghOTcctFJJXtFWzDU9h3FThgq88NoXdNW1tg5Y4XsHW8gp1ybY-fkw9q7j9MhXzPr0SeLw2ACTkvSjWolUCYyWK-gjVNKEXudzx1NPGoK-lG13ulVtX5UrUHorDrH3p36l25E9xQ6uc3A-xNgkjVDH02wPj1xilGpeJu5TyuH2cZvj1En6zFYdD6inbWb_P8v-QvIlqKR</recordid><startdate>20061001</startdate><enddate>20061001</enddate><creator>Cope, H.</creator><creator>Mutter, R.</creator><creator>Heal, W.</creator><creator>Pascoe, C.</creator><creator>Brown, P.</creator><creator>Pratt, S.</creator><creator>Chen, B.</creator><general>Elsevier Masson SAS</general><general>Elsevier</general><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>20061001</creationdate><title>Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents</title><author>Cope, H. ; Mutter, R. ; Heal, W. ; Pascoe, C. ; Brown, P. ; Pratt, S. ; Chen, B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-cc48085733c35b787f8190a1cfb1eb5a17b5a21441974ebdac57fd360808d9733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Acridine</topic><topic>Acridines - chemical synthesis</topic><topic>Acridines - chemistry</topic><topic>Acridines - pharmacology</topic><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Miscellaneous</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Prion protein</topic><topic>Prions - antagonists & inhibitors</topic><topic>Quinaldines - chemical synthesis</topic><topic>Quinaldines - chemistry</topic><topic>Quinaldines - pharmacology</topic><topic>Quinazoline</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - chemistry</topic><topic>Quinazolines - pharmacology</topic><topic>Quinoline</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>TSE</topic><topic>vCJD</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cope, H.</creatorcontrib><creatorcontrib>Mutter, R.</creatorcontrib><creatorcontrib>Heal, W.</creatorcontrib><creatorcontrib>Pascoe, C.</creatorcontrib><creatorcontrib>Brown, P.</creatorcontrib><creatorcontrib>Pratt, S.</creatorcontrib><creatorcontrib>Chen, B.</creatorcontrib><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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cope, H.</au><au>Mutter, R.</au><au>Heal, W.</au><au>Pascoe, C.</au><au>Brown, P.</au><au>Pratt, S.</au><au>Chen, B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2006-10-01</date><risdate>2006</risdate><volume>41</volume><issue>10</issue><spage>1124</spage><epage>1143</epage><pages>1124-1143</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><coden>EJMCA5</coden><abstract>Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP
Sc, which is a misfolded isoform of the normal cellular prion protein PrP
C. Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP
C and the suppression of PrP
Sc accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC
50s in the nanomolar range.</abstract><cop>Oxford</cop><pub>Elsevier Masson SAS</pub><pmid>16782236</pmid><doi>10.1016/j.ejmech.2006.05.002</doi><tpages>20</tpages></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2006-10, Vol.41 (10), p.1124-1143 |
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| subjects | Acridine Acridines - chemical synthesis Acridines - chemistry Acridines - pharmacology Animals Binding, Competitive Biological and medical sciences Cell Line Cell Survival - drug effects Dose-Response Relationship, Drug Drug Evaluation, Preclinical Medical sciences Mice Miscellaneous Molecular Structure Neuropharmacology Pharmacology. Drug treatments Prion protein Prions - antagonists & inhibitors Quinaldines - chemical synthesis Quinaldines - chemistry Quinaldines - pharmacology Quinazoline Quinazolines - chemical synthesis Quinazolines - chemistry Quinazolines - pharmacology Quinoline Stereoisomerism Structure-Activity Relationship TSE vCJD |
| title | Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents |
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