Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase

A direct method for the preparation of 5‘-S-alkynyl-5‘-thioadenosine and 5‘-S-allenyl-5‘-thioadenosine has been developed. Treatment of a protected 5‘-acetylthio-5‘-deoxyadenosine with sodium methoxide and propargyl bromide followed by deprotection gave the 5‘-S-propargyl-5‘-thioadenosine 4. Under c...

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Veröffentlicht in:Journal of medicinal chemistry 2001-08, Vol.44 (17), p.2743-2752
Hauptverfasser: Guillerm, Georges, Guillerm, Danielle, Vandenplas-Witkowki, Corinne, Rogniaux, Hélène, Carte, Nathalie, Leize, Emmanuelle, Van Dorsselaer, Alain, De Clercq, Erik, Lambert, Christine
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container_end_page 2752
container_issue 17
container_start_page 2743
container_title Journal of medicinal chemistry
container_volume 44
creator Guillerm, Georges
Guillerm, Danielle
Vandenplas-Witkowki, Corinne
Rogniaux, Hélène
Carte, Nathalie
Leize, Emmanuelle
Van Dorsselaer, Alain
De Clercq, Erik
Lambert, Christine
description A direct method for the preparation of 5‘-S-alkynyl-5‘-thioadenosine and 5‘-S-allenyl-5‘-thioadenosine has been developed. Treatment of a protected 5‘-acetylthio-5‘-deoxyadenosine with sodium methoxide and propargyl bromide followed by deprotection gave the 5‘-S-propargyl-5‘-thioadenosine 4. Under controlled base-catalysis with sodium tert-butoxide in tert-butyl alcohol 4 was quantitatively converted into 5‘-S-allenyl-5‘-thioadenosine 5 or 5‘-S-propynyl-5‘-thioadenosine 6. Incubation of recombinant human placental AdoHcy hydrolase with 4, 5, or 6 resulted in time- and concentration-dependent inactivation of the enzyme (K i: 45 ± 0.5, 16 ± 1, and 15 ± 1 μM, respectively). Compound 4 caused complete conversion of the enzyme from its E-NAD+ to E-NADH form during the inactivation process. This indicates that 4 is a substrate for the 3‘-oxidative activity of AdoHcy hydrolase (type I inhibitor). In contrast, the NAD+/NADH content of the enzyme was not affected during the inactivation process with 5 and 6, and their mechanism of inactivation was further investigated. Addition of enzyme-sequestered water on the S-allenylthio group of 5 or S-propynylthio group of 6 within the active site should lead to the formation of the corresponding thioester 7. This acylating-intermediate agent could then undergo nucleophilic attack by a protein residue, leading to a type II mechanism-based inactivation. ElectroSpray mass spectra analysis of the inactivated protein by 5 supports this mechanistic proposal. Further studies (MALDI-TOF and ESI/MSn experiments) of the trypsin and endo-Lys-C proteolytic cleavage of the fragments of inactivated AdoHcy hydrolase by 5 were carried out for localization of the labeling. The antiviral activity of 4, 5, and 6 against a large variety of viruses was determined. Significant activity (EC50: 1.9 μM) was noted with 5 against vaccinia virus.
doi_str_mv 10.1021/jm0108350
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Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Cell Line ; Chromatography, Liquid ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Hydrolases - antagonists &amp; inhibitors ; Medical sciences ; Models, Molecular ; Molecular Sequence Data ; NAD - analysis ; Pharmacology. Drug treatments ; Placenta - enzymology ; Recombinant Proteins - antagonists &amp; inhibitors ; S-Adenosyl-L-homocysteine hydrolase ; Spectrometry, Mass, Electrospray Ionization ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Structure-Activity Relationship ; Thionucleosides - chemical synthesis ; Thionucleosides - chemistry ; Thionucleosides - pharmacology ; Vaccinia virus</subject><ispartof>Journal of medicinal chemistry, 2001-08, Vol.44 (17), p.2743-2752</ispartof><rights>Copyright © 2001 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a409t-e5820f556f0369667c03e13447190ec882be843a4be957ec8a9571e50f649b4b3</citedby><cites>FETCH-LOGICAL-a409t-e5820f556f0369667c03e13447190ec882be843a4be957ec8a9571e50f649b4b3</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/jm0108350$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0108350$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=1107703$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11495586$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guillerm, Georges</creatorcontrib><creatorcontrib>Guillerm, Danielle</creatorcontrib><creatorcontrib>Vandenplas-Witkowki, Corinne</creatorcontrib><creatorcontrib>Rogniaux, Hélène</creatorcontrib><creatorcontrib>Carte, Nathalie</creatorcontrib><creatorcontrib>Leize, Emmanuelle</creatorcontrib><creatorcontrib>Van Dorsselaer, Alain</creatorcontrib><creatorcontrib>De Clercq, Erik</creatorcontrib><creatorcontrib>Lambert, Christine</creatorcontrib><title>Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A direct method for the preparation of 5‘-S-alkynyl-5‘-thioadenosine and 5‘-S-allenyl-5‘-thioadenosine has been developed. Treatment of a protected 5‘-acetylthio-5‘-deoxyadenosine with sodium methoxide and propargyl bromide followed by deprotection gave the 5‘-S-propargyl-5‘-thioadenosine 4. Under controlled base-catalysis with sodium tert-butoxide in tert-butyl alcohol 4 was quantitatively converted into 5‘-S-allenyl-5‘-thioadenosine 5 or 5‘-S-propynyl-5‘-thioadenosine 6. Incubation of recombinant human placental AdoHcy hydrolase with 4, 5, or 6 resulted in time- and concentration-dependent inactivation of the enzyme (K i: 45 ± 0.5, 16 ± 1, and 15 ± 1 μM, respectively). Compound 4 caused complete conversion of the enzyme from its E-NAD+ to E-NADH form during the inactivation process. This indicates that 4 is a substrate for the 3‘-oxidative activity of AdoHcy hydrolase (type I inhibitor). In contrast, the NAD+/NADH content of the enzyme was not affected during the inactivation process with 5 and 6, and their mechanism of inactivation was further investigated. Addition of enzyme-sequestered water on the S-allenylthio group of 5 or S-propynylthio group of 6 within the active site should lead to the formation of the corresponding thioester 7. This acylating-intermediate agent could then undergo nucleophilic attack by a protein residue, leading to a type II mechanism-based inactivation. ElectroSpray mass spectra analysis of the inactivated protein by 5 supports this mechanistic proposal. Further studies (MALDI-TOF and ESI/MSn experiments) of the trypsin and endo-Lys-C proteolytic cleavage of the fragments of inactivated AdoHcy hydrolase by 5 were carried out for localization of the labeling. The antiviral activity of 4, 5, and 6 against a large variety of viruses was determined. Significant activity (EC50: 1.9 μM) was noted with 5 against vaccinia virus.</description><subject>5'-S-Allenyl-5'-thioadenosine</subject><subject>5'-S-Propargyl-5'-thioadenosine</subject><subject>5'-S-Propynyl-5'-thioadenosine</subject><subject>Adenosylhomocysteinase</subject><subject>Amino Acid Sequence</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Chromatography, Liquid</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydrolases - antagonists &amp; inhibitors</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>NAD - analysis</subject><subject>Pharmacology. Drug treatments</subject><subject>Placenta - enzymology</subject><subject>Recombinant Proteins - antagonists &amp; inhibitors</subject><subject>S-Adenosyl-L-homocysteine hydrolase</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</subject><subject>Structure-Activity Relationship</subject><subject>Thionucleosides - chemical synthesis</subject><subject>Thionucleosides - chemistry</subject><subject>Thionucleosides - pharmacology</subject><subject>Vaccinia virus</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c1u1DAQAGALgehSOPACKAdAQmpgHNv5OW5XLVtRClIKV8txJloviV3s7Ja8Bw-Mt7tqOSBxGnn8ecaaIeQlhfcUMvphPQCFkgl4RGZUZJDyEvhjMgPIsjTLM3ZEnoWwBgBGM_aUHFHKKyHKfEZ-15MdVxhMOEk-o14pa8KQuC6Z69E4e5Io2yZzO5qt8aq_y27NOO2ESq7wNqnRGwy788JtVY92fKiTnqqAbXJhV6Yxo_N3rE7nLVoXpj7t06UbnJ7CiMZispxa7_r45Dl50qk-4ItDPCbfzs-uF8v08svHi8X8MlUcqjFFUWbQCZF3wPIqzwsNDCnjvKAVoC7LrMGSM8UbrEQREyoGigK6nFcNb9gxebuve-Pdzw2GUQ4maOx7ZdFtgiziVCll2X8hLRkUooAI3-2h9i4Ej5288WZQfpIU5G5X8n5X0b46FN00A7YP8rCcCF4fgApa9Z1XVpvwl4Mitows3TMT5_jr_lr5HzIvWCHk9ddanlenNf1-VctP0b_Ze6WDXLuNt3HG__jfHz6Ote0</recordid><startdate>20010816</startdate><enddate>20010816</enddate><creator>Guillerm, Georges</creator><creator>Guillerm, Danielle</creator><creator>Vandenplas-Witkowki, Corinne</creator><creator>Rogniaux, Hélène</creator><creator>Carte, Nathalie</creator><creator>Leize, Emmanuelle</creator><creator>Van Dorsselaer, Alain</creator><creator>De Clercq, Erik</creator><creator>Lambert, Christine</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>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20010816</creationdate><title>Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase</title><author>Guillerm, Georges ; Guillerm, Danielle ; Vandenplas-Witkowki, Corinne ; Rogniaux, Hélène ; Carte, Nathalie ; Leize, Emmanuelle ; Van Dorsselaer, Alain ; De Clercq, Erik ; Lambert, Christine</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a409t-e5820f556f0369667c03e13447190ec882be843a4be957ec8a9571e50f649b4b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>5'-S-Allenyl-5'-thioadenosine</topic><topic>5'-S-Propargyl-5'-thioadenosine</topic><topic>5'-S-Propynyl-5'-thioadenosine</topic><topic>Adenosylhomocysteinase</topic><topic>Amino Acid Sequence</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Chromatography, Liquid</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydrolases - antagonists &amp; inhibitors</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>NAD - analysis</topic><topic>Pharmacology. Drug treatments</topic><topic>Placenta - enzymology</topic><topic>Recombinant Proteins - antagonists &amp; inhibitors</topic><topic>S-Adenosyl-L-homocysteine hydrolase</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</topic><topic>Structure-Activity Relationship</topic><topic>Thionucleosides - chemical synthesis</topic><topic>Thionucleosides - chemistry</topic><topic>Thionucleosides - pharmacology</topic><topic>Vaccinia virus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guillerm, Georges</creatorcontrib><creatorcontrib>Guillerm, Danielle</creatorcontrib><creatorcontrib>Vandenplas-Witkowki, Corinne</creatorcontrib><creatorcontrib>Rogniaux, Hélène</creatorcontrib><creatorcontrib>Carte, Nathalie</creatorcontrib><creatorcontrib>Leize, Emmanuelle</creatorcontrib><creatorcontrib>Van Dorsselaer, Alain</creatorcontrib><creatorcontrib>De Clercq, Erik</creatorcontrib><creatorcontrib>Lambert, Christine</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>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research 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>Guillerm, Georges</au><au>Guillerm, Danielle</au><au>Vandenplas-Witkowki, Corinne</au><au>Rogniaux, Hélène</au><au>Carte, Nathalie</au><au>Leize, Emmanuelle</au><au>Van Dorsselaer, Alain</au><au>De Clercq, Erik</au><au>Lambert, Christine</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-08-16</date><risdate>2001</risdate><volume>44</volume><issue>17</issue><spage>2743</spage><epage>2752</epage><pages>2743-2752</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A direct method for the preparation of 5‘-S-alkynyl-5‘-thioadenosine and 5‘-S-allenyl-5‘-thioadenosine has been developed. Treatment of a protected 5‘-acetylthio-5‘-deoxyadenosine with sodium methoxide and propargyl bromide followed by deprotection gave the 5‘-S-propargyl-5‘-thioadenosine 4. Under controlled base-catalysis with sodium tert-butoxide in tert-butyl alcohol 4 was quantitatively converted into 5‘-S-allenyl-5‘-thioadenosine 5 or 5‘-S-propynyl-5‘-thioadenosine 6. Incubation of recombinant human placental AdoHcy hydrolase with 4, 5, or 6 resulted in time- and concentration-dependent inactivation of the enzyme (K i: 45 ± 0.5, 16 ± 1, and 15 ± 1 μM, respectively). Compound 4 caused complete conversion of the enzyme from its E-NAD+ to E-NADH form during the inactivation process. This indicates that 4 is a substrate for the 3‘-oxidative activity of AdoHcy hydrolase (type I inhibitor). In contrast, the NAD+/NADH content of the enzyme was not affected during the inactivation process with 5 and 6, and their mechanism of inactivation was further investigated. Addition of enzyme-sequestered water on the S-allenylthio group of 5 or S-propynylthio group of 6 within the active site should lead to the formation of the corresponding thioester 7. This acylating-intermediate agent could then undergo nucleophilic attack by a protein residue, leading to a type II mechanism-based inactivation. ElectroSpray mass spectra analysis of the inactivated protein by 5 supports this mechanistic proposal. Further studies (MALDI-TOF and ESI/MSn experiments) of the trypsin and endo-Lys-C proteolytic cleavage of the fragments of inactivated AdoHcy hydrolase by 5 were carried out for localization of the labeling. The antiviral activity of 4, 5, and 6 against a large variety of viruses was determined. Significant activity (EC50: 1.9 μM) was noted with 5 against vaccinia virus.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11495586</pmid><doi>10.1021/jm0108350</doi><tpages>10</tpages></addata></record>
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subjects 5'-S-Allenyl-5'-thioadenosine
5'-S-Propargyl-5'-thioadenosine
5'-S-Propynyl-5'-thioadenosine
Adenosylhomocysteinase
Amino Acid Sequence
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Biological and medical sciences
Cell Line
Chromatography, Liquid
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Hydrolases - antagonists & inhibitors
Medical sciences
Models, Molecular
Molecular Sequence Data
NAD - analysis
Pharmacology. Drug treatments
Placenta - enzymology
Recombinant Proteins - antagonists & inhibitors
S-Adenosyl-L-homocysteine hydrolase
Spectrometry, Mass, Electrospray Ionization
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Structure-Activity Relationship
Thionucleosides - chemical synthesis
Thionucleosides - chemistry
Thionucleosides - pharmacology
Vaccinia virus
title Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase
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