5-(Halomethyl)-2-pyranones as irreversible inhibitors of .alpha.-chymotrypsin
A series of 5-(halomethyl)-2-pyranones were prepared and assayed as potential mechanism-based inhibitors of chymotrypsin, in order to test whether substitution of a suitable electron-withdrawing group at position 5 in a 2-pyranone can activate the ring for catalytic hydrolysis, as well as form a mec...
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| Veröffentlicht in: | Journal of medicinal chemistry 1986-08, Vol.29 (8), p.1483-1487 |
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| container_title | Journal of medicinal chemistry |
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| creator | Boulanger, William A Katzenellenbogen, John A |
| description | A series of 5-(halomethyl)-2-pyranones were prepared and assayed as potential mechanism-based inhibitors of chymotrypsin, in order to test whether substitution of a suitable electron-withdrawing group at position 5 in a 2-pyranone can activate the ring for catalytic hydrolysis, as well as form a mechanism-based inhibitor. 3-Benzyl-5-(chloromethyl)-2-pyranone (3) and 3-(1-naphthylmethyl)-5-(chloromethyl)-2-pyranone (4) rapidly and irreversibly inactivate chymotrypsin with high efficiency (I/E = 2.0 for 3 and 1.38 for 4). However, evidence for their formation of an acyl enzyme is lacking, and thus they may simply be active-site alkylating agents. 6-Methyl substitution on 4, or replacement of the chloromethyl of 3 with CF3, prevents inactivation. Since 6-bromo substitution is capable of ring activation, but 5-bromo substitution (3-benzyl-5-bromo-2-pyranone (11)) is not, the 5-position of the pyrone does not appear to affect catalytic hydrolysis. |
| doi_str_mv | 10.1021/jm00158a027 |
| format | Article |
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However, evidence for their formation of an acyl enzyme is lacking, and thus they may simply be active-site alkylating agents. 6-Methyl substitution on 4, or replacement of the chloromethyl of 3 with CF3, prevents inactivation. Since 6-bromo substitution is capable of ring activation, but 5-bromo substitution (3-benzyl-5-bromo-2-pyranone (11)) is not, the 5-position of the pyrone does not appear to affect catalytic hydrolysis.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00158a027</identifier><identifier>PMID: 3735315</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Alkylation ; Chemistry ; Chymotrypsin - antagonists & inhibitors ; Exact sciences and technology ; Half-Life ; Heterocyclic compounds ; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives ; Mercaptoethanol - metabolism ; Organic chemistry ; Preparations and properties ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - pharmacology ; Pyrans - chemical synthesis ; Pyrones - chemical synthesis ; Pyrones - pharmacology ; Structure-Activity Relationship ; Time Factors</subject><ispartof>Journal of medicinal chemistry, 1986-08, Vol.29 (8), p.1483-1487</ispartof><rights>1987 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-a4adb342b30aadcff719ad395a86da7eb520a9878160e9383e7bccdc3f2eec303</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/jm00158a027$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00158a027$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7893302$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3735315$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Boulanger, William A</creatorcontrib><creatorcontrib>Katzenellenbogen, John A</creatorcontrib><title>5-(Halomethyl)-2-pyranones as irreversible inhibitors of .alpha.-chymotrypsin</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 5-(halomethyl)-2-pyranones were prepared and assayed as potential mechanism-based inhibitors of chymotrypsin, in order to test whether substitution of a suitable electron-withdrawing group at position 5 in a 2-pyranone can activate the ring for catalytic hydrolysis, as well as form a mechanism-based inhibitor. 3-Benzyl-5-(chloromethyl)-2-pyranone (3) and 3-(1-naphthylmethyl)-5-(chloromethyl)-2-pyranone (4) rapidly and irreversibly inactivate chymotrypsin with high efficiency (I/E = 2.0 for 3 and 1.38 for 4). However, evidence for their formation of an acyl enzyme is lacking, and thus they may simply be active-site alkylating agents. 6-Methyl substitution on 4, or replacement of the chloromethyl of 3 with CF3, prevents inactivation. Since 6-bromo substitution is capable of ring activation, but 5-bromo substitution (3-benzyl-5-bromo-2-pyranone (11)) is not, the 5-position of the pyrone does not appear to affect catalytic hydrolysis.</description><subject>Alkylation</subject><subject>Chemistry</subject><subject>Chymotrypsin - antagonists & inhibitors</subject><subject>Exact sciences and technology</subject><subject>Half-Life</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives</subject><subject>Mercaptoethanol - metabolism</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Pyrans - chemical synthesis</subject><subject>Pyrones - chemical synthesis</subject><subject>Pyrones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Time Factors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1986</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEFv1DAQRi0EKkvhxBkpB1RAyMvY3sTJEQptEVtRQZG4WRPH0XpJ4uDJIvLvcbWrVQ-c5vA9fTPzGHsuYClAinfbHkDkJYLUD9hC5BL4qoTVQ7YAkJLLQqrH7AnRFgCUkOqEnSitciXyBbvO-esr7ELvps3cveGSj3PEIQyOMqTMx-j-uEi-7lzmh42v_RQiZaHNltiNG1xyu5n7MMV5JD88ZY9a7Mg9O8xT9uPi0-35FV9_vfx8_n7NMS2dOK6wqdVK1goQG9u2WlTYqCrHsmhQuzq9gFWpS1GAq1SpnK6tbaxqpXNWgTplZ_veMYbfO0eT6T1Z13U4uLAjo4uqkHlZJfDtHrQxEEXXmjH6HuNsBJg7eeaevES_ONTu6t41R_ZgK-UvDzmSxa5NoqynI6bTQgUyYXyPeZrc32OM8ZcptNK5ub35br6sb75dVx9-mo-Jf7Xn0ZLZhl0ckrv_HvgPomySlA</recordid><startdate>19860801</startdate><enddate>19860801</enddate><creator>Boulanger, William A</creator><creator>Katzenellenbogen, John 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>19860801</creationdate><title>5-(Halomethyl)-2-pyranones as irreversible inhibitors of .alpha.-chymotrypsin</title><author>Boulanger, William A ; Katzenellenbogen, John A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-a4adb342b30aadcff719ad395a86da7eb520a9878160e9383e7bccdc3f2eec303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1986</creationdate><topic>Alkylation</topic><topic>Chemistry</topic><topic>Chymotrypsin - antagonists & inhibitors</topic><topic>Exact sciences and technology</topic><topic>Half-Life</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives</topic><topic>Mercaptoethanol - metabolism</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Pyrans - chemical synthesis</topic><topic>Pyrones - chemical synthesis</topic><topic>Pyrones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boulanger, William A</creatorcontrib><creatorcontrib>Katzenellenbogen, John 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>Boulanger, William A</au><au>Katzenellenbogen, John A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-(Halomethyl)-2-pyranones as irreversible inhibitors of .alpha.-chymotrypsin</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1986-08-01</date><risdate>1986</risdate><volume>29</volume><issue>8</issue><spage>1483</spage><epage>1487</epage><pages>1483-1487</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 5-(halomethyl)-2-pyranones were prepared and assayed as potential mechanism-based inhibitors of chymotrypsin, in order to test whether substitution of a suitable electron-withdrawing group at position 5 in a 2-pyranone can activate the ring for catalytic hydrolysis, as well as form a mechanism-based inhibitor. 3-Benzyl-5-(chloromethyl)-2-pyranone (3) and 3-(1-naphthylmethyl)-5-(chloromethyl)-2-pyranone (4) rapidly and irreversibly inactivate chymotrypsin with high efficiency (I/E = 2.0 for 3 and 1.38 for 4). However, evidence for their formation of an acyl enzyme is lacking, and thus they may simply be active-site alkylating agents. 6-Methyl substitution on 4, or replacement of the chloromethyl of 3 with CF3, prevents inactivation. Since 6-bromo substitution is capable of ring activation, but 5-bromo substitution (3-benzyl-5-bromo-2-pyranone (11)) is not, the 5-position of the pyrone does not appear to affect catalytic hydrolysis.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>3735315</pmid><doi>10.1021/jm00158a027</doi><tpages>5</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1986-08, Vol.29 (8), p.1483-1487 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Alkylation Chemistry Chymotrypsin - antagonists & inhibitors Exact sciences and technology Half-Life Heterocyclic compounds Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives Mercaptoethanol - metabolism Organic chemistry Preparations and properties Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacology Pyrans - chemical synthesis Pyrones - chemical synthesis Pyrones - pharmacology Structure-Activity Relationship Time Factors |
| title | 5-(Halomethyl)-2-pyranones as irreversible inhibitors of .alpha.-chymotrypsin |
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