Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors
We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-12, Vol.22 (24), p.7486-7489 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Chiba, Takashi Ohwada, Jun Sakamoto, Hiroshi Kobayashi, Takamitsu Fukami, Takaaki A. Irie, Machiko Miura, Takaaki Ohara, Kazuhiro Koyano, Hiroshi |
| description | We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole’s 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters. |
| doi_str_mv | 10.1016/j.bmcl.2012.10.045 |
| format | Article |
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Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole’s 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.10.045</identifier><identifier>PMID: 23122816</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>7-Azaindole ; Biological and medical sciences ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzymes ; Glutathione ; Glyoxalase I (GLO1) ; high-throughput screening ; Humans ; Indole ; Indoles - chemistry ; Ionizing radiation ; Lactoylglutathione lyase ; Lactoylglutathione Lyase - antagonists & inhibitors ; Lactoylglutathione Lyase - metabolism ; Medical sciences ; Models, Molecular ; Molecular Structure ; N-Hydroxypyridone ; Pharmacology. Drug treatments ; Pyridones - chemical synthesis ; Pyridones - chemistry ; Pyridones - pharmacology ; screening ; Structure-Activity Relationship ; Structure-activity relationships ; Structure-based drug design (SBDD) ; Thermodynamics ; X-radiation ; X-ray crystallography ; X-ray diffraction</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-12, Vol.22 (24), p.7486-7489</ispartof><rights>2012 Elsevier Ltd</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-989c8a13793e059c1736ff5c01ae195992103c235ced9811dc0b30b046c45a343</citedby><cites>FETCH-LOGICAL-c443t-989c8a13793e059c1736ff5c01ae195992103c235ced9811dc0b30b046c45a343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X12013236$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26727640$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23122816$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chiba, Takashi</creatorcontrib><creatorcontrib>Ohwada, Jun</creatorcontrib><creatorcontrib>Sakamoto, Hiroshi</creatorcontrib><creatorcontrib>Kobayashi, Takamitsu</creatorcontrib><creatorcontrib>Fukami, Takaaki A.</creatorcontrib><creatorcontrib>Irie, Machiko</creatorcontrib><creatorcontrib>Miura, Takaaki</creatorcontrib><creatorcontrib>Ohara, Kazuhiro</creatorcontrib><creatorcontrib>Koyano, Hiroshi</creatorcontrib><title>Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole’s 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.</description><subject>7-Azaindole</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzymes</subject><subject>Glutathione</subject><subject>Glyoxalase I (GLO1)</subject><subject>high-throughput screening</subject><subject>Humans</subject><subject>Indole</subject><subject>Indoles - chemistry</subject><subject>Ionizing radiation</subject><subject>Lactoylglutathione lyase</subject><subject>Lactoylglutathione Lyase - antagonists & inhibitors</subject><subject>Lactoylglutathione Lyase - metabolism</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>N-Hydroxypyridone</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyridones - chemical synthesis</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - pharmacology</subject><subject>screening</subject><subject>Structure-Activity Relationship</subject><subject>Structure-activity relationships</subject><subject>Structure-based drug design (SBDD)</subject><subject>Thermodynamics</subject><subject>X-radiation</subject><subject>X-ray crystallography</subject><subject>X-ray diffraction</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU2LFDEQhoMo7rj6BzxoLoKXHiuf0wEvsn4tLHrQBQ9CqE6nZzP0dMake9n215tmRr2J5FBQPPWmqIeQpwzWDJh-tVs3e9evOTBeGmuQ6h5ZMallJSSo-2QFRkNVG_ntjDzKeQfAJEj5kJxxwTivmV6R7299DtuB4tBSf4v9hGOIA40dxZ8Yhjb2vspTk8cwTqNv6afqZm5TvJsPcwptHHymmOm2n-Md9pg9vaRhuAlNGGPKj8mDDvvsn5zqObl-_-7rxcfq6vOHy4s3V5WTUoyVqY2rkYmNER6UcWwjdNcpBww9M8oYzkA4LpTzrakZax00AhqQ2kmFQopz8vKYe0jxx-TzaPchO9_3OPg4Zcv4pjwhQP8HykFoqdSmoPyIuhRzTr6zhxT2mGbLwC4C7M4uAuwiYOkVAWXo2Sl_ava-_TPy--IFeHECMDvsu4SDC_kvp8uqWkLhnh-5DqPFbSrM9ZfykyoWRfG4JL0-Er6c9jb4ZLMLfihHCsm70bYx_GvTXwisrGU</recordid><startdate>20121215</startdate><enddate>20121215</enddate><creator>Chiba, Takashi</creator><creator>Ohwada, Jun</creator><creator>Sakamoto, Hiroshi</creator><creator>Kobayashi, Takamitsu</creator><creator>Fukami, Takaaki A.</creator><creator>Irie, Machiko</creator><creator>Miura, Takaaki</creator><creator>Ohara, Kazuhiro</creator><creator>Koyano, Hiroshi</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20121215</creationdate><title>Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors</title><author>Chiba, Takashi ; Ohwada, Jun ; Sakamoto, Hiroshi ; Kobayashi, Takamitsu ; Fukami, Takaaki A. ; Irie, Machiko ; Miura, Takaaki ; Ohara, Kazuhiro ; Koyano, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-989c8a13793e059c1736ff5c01ae195992103c235ced9811dc0b30b046c45a343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>7-Azaindole</topic><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzymes</topic><topic>Glutathione</topic><topic>Glyoxalase I (GLO1)</topic><topic>high-throughput screening</topic><topic>Humans</topic><topic>Indole</topic><topic>Indoles - chemistry</topic><topic>Ionizing radiation</topic><topic>Lactoylglutathione lyase</topic><topic>Lactoylglutathione Lyase - antagonists & inhibitors</topic><topic>Lactoylglutathione Lyase - metabolism</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>N-Hydroxypyridone</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyridones - chemical synthesis</topic><topic>Pyridones - chemistry</topic><topic>Pyridones - pharmacology</topic><topic>screening</topic><topic>Structure-Activity Relationship</topic><topic>Structure-activity relationships</topic><topic>Structure-based drug design (SBDD)</topic><topic>Thermodynamics</topic><topic>X-radiation</topic><topic>X-ray crystallography</topic><topic>X-ray diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chiba, Takashi</creatorcontrib><creatorcontrib>Ohwada, Jun</creatorcontrib><creatorcontrib>Sakamoto, Hiroshi</creatorcontrib><creatorcontrib>Kobayashi, Takamitsu</creatorcontrib><creatorcontrib>Fukami, Takaaki A.</creatorcontrib><creatorcontrib>Irie, Machiko</creatorcontrib><creatorcontrib>Miura, Takaaki</creatorcontrib><creatorcontrib>Ohara, Kazuhiro</creatorcontrib><creatorcontrib>Koyano, Hiroshi</creatorcontrib><collection>AGRIS</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chiba, Takashi</au><au>Ohwada, Jun</au><au>Sakamoto, Hiroshi</au><au>Kobayashi, Takamitsu</au><au>Fukami, Takaaki A.</au><au>Irie, Machiko</au><au>Miura, Takaaki</au><au>Ohara, Kazuhiro</au><au>Koyano, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-12-15</date><risdate>2012</risdate><volume>22</volume><issue>24</issue><spage>7486</spage><epage>7489</epage><pages>7486-7489</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole’s 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>23122816</pmid><doi>10.1016/j.bmcl.2012.10.045</doi><tpages>4</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2012-12, Vol.22 (24), p.7486-7489 |
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| subjects | 7-Azaindole Biological and medical sciences Crystallography, X-Ray Dose-Response Relationship, Drug Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzymes Glutathione Glyoxalase I (GLO1) high-throughput screening Humans Indole Indoles - chemistry Ionizing radiation Lactoylglutathione lyase Lactoylglutathione Lyase - antagonists & inhibitors Lactoylglutathione Lyase - metabolism Medical sciences Models, Molecular Molecular Structure N-Hydroxypyridone Pharmacology. Drug treatments Pyridones - chemical synthesis Pyridones - chemistry Pyridones - pharmacology screening Structure-Activity Relationship Structure-activity relationships Structure-based drug design (SBDD) Thermodynamics X-radiation X-ray crystallography X-ray diffraction |
| title | Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors |
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