Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents
Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-05, Vol.55 (10), p.4837-4846 |
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| creator | Zheng, Suqing Santosh Laxmi, Y. R David, Emilie Dinkova-Kostova, Albena T Shiavoni, Katherine H Ren, Yanqing Zheng, Ying Trevino, Isaac Bumeister, Ronald Ojima, Iwao Wigley, W. Christian Bliska, James B Mierke, Dale F Honda, Tadashi |
| description | Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31. |
| doi_str_mv | 10.1021/jm3003922 |
| format | Article |
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R ; David, Emilie ; Dinkova-Kostova, Albena T ; Shiavoni, Katherine H ; Ren, Yanqing ; Zheng, Ying ; Trevino, Isaac ; Bumeister, Ronald ; Ojima, Iwao ; Wigley, W. Christian ; Bliska, James B ; Mierke, Dale F ; Honda, Tadashi</creator><creatorcontrib>Zheng, Suqing ; Santosh Laxmi, Y. R ; David, Emilie ; Dinkova-Kostova, Albena T ; Shiavoni, Katherine H ; Ren, Yanqing ; Zheng, Ying ; Trevino, Isaac ; Bumeister, Ronald ; Ojima, Iwao ; Wigley, W. Christian ; Bliska, James B ; Mierke, Dale F ; Honda, Tadashi</creatorcontrib><description>Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm3003922</identifier><identifier>PMID: 22533790</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alkynes - chemical synthesis ; Alkynes - chemistry ; Alkynes - pharmacology ; Amides - chemistry ; Amides - pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anticarcinogenic Agents - chemical synthesis ; Anticarcinogenic Agents - chemistry ; Anticarcinogenic Agents - pharmacology ; Apoptosis - drug effects ; Cell Line ; Cell Line, Tumor ; Cytoprotection ; I-kappa B Kinase - antagonists & inhibitors ; Interleukin-1beta - metabolism ; Lipopolysaccharides - pharmacology ; Macrophages - cytology ; Macrophages - drug effects ; Macrophages - metabolism ; Mice ; NAD(P)H Dehydrogenase (Quinone) - biosynthesis ; Nitric Oxide - antagonists & inhibitors ; Nitric Oxide - biosynthesis ; Nitriles - chemical synthesis ; Nitriles - chemistry ; Nitriles - pharmacology ; Oleanolic Acid - analogs & derivatives ; Oleanolic Acid - chemistry ; Oleanolic Acid - pharmacology ; Phenanthrenes - chemistry ; Phenanthrenes - pharmacology ; Thiophenes - chemistry ; Thiophenes - pharmacology ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Journal of medicinal chemistry, 2012-05, Vol.55 (10), p.4837-4846</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-d1f00f529fe2dadd8be23520647dd1a36b0d45c763c93db137e2072496d0f83a3</citedby><cites>FETCH-LOGICAL-a381t-d1f00f529fe2dadd8be23520647dd1a36b0d45c763c93db137e2072496d0f83a3</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/jm3003922$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm3003922$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22533790$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Suqing</creatorcontrib><creatorcontrib>Santosh Laxmi, Y. R</creatorcontrib><creatorcontrib>David, Emilie</creatorcontrib><creatorcontrib>Dinkova-Kostova, Albena T</creatorcontrib><creatorcontrib>Shiavoni, Katherine H</creatorcontrib><creatorcontrib>Ren, Yanqing</creatorcontrib><creatorcontrib>Zheng, Ying</creatorcontrib><creatorcontrib>Trevino, Isaac</creatorcontrib><creatorcontrib>Bumeister, Ronald</creatorcontrib><creatorcontrib>Ojima, Iwao</creatorcontrib><creatorcontrib>Wigley, W. Christian</creatorcontrib><creatorcontrib>Bliska, James B</creatorcontrib><creatorcontrib>Mierke, Dale F</creatorcontrib><creatorcontrib>Honda, Tadashi</creatorcontrib><title>Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.</description><subject>Alkynes - chemical synthesis</subject><subject>Alkynes - chemistry</subject><subject>Alkynes - pharmacology</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Anticarcinogenic Agents - chemical synthesis</subject><subject>Anticarcinogenic Agents - chemistry</subject><subject>Anticarcinogenic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cytoprotection</subject><subject>I-kappa B Kinase - antagonists & inhibitors</subject><subject>Interleukin-1beta - metabolism</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>NAD(P)H Dehydrogenase (Quinone) - biosynthesis</subject><subject>Nitric Oxide - antagonists & inhibitors</subject><subject>Nitric Oxide - biosynthesis</subject><subject>Nitriles - chemical synthesis</subject><subject>Nitriles - chemistry</subject><subject>Nitriles - pharmacology</subject><subject>Oleanolic Acid - analogs & derivatives</subject><subject>Oleanolic Acid - chemistry</subject><subject>Oleanolic Acid - pharmacology</subject><subject>Phenanthrenes - chemistry</subject><subject>Phenanthrenes - pharmacology</subject><subject>Thiophenes - chemistry</subject><subject>Thiophenes - pharmacology</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0ctqGzEUBmARGmo36aIvULQppNBJdBnPZekOuYFzIW3WgyydsWU0kjuSA3qlPGXk2PUqK22-83OOfoS-UXJOCaMXq54TwmvGjtCYThjJ8orkn9CYEMYyVjA-Ql-8X5GEKOOf0YixCedlTcbo9U-0YQle-1-4WUKvpTD4CYQM-kWHiIXHd1ouBRg8lRLWwQ1JCqvwb-2MW7z7RxfAyohdh--cdTJKoyVuorAOrLOQJu7dS4rYzt3oxdLE3UzAUxt0pm1nRN-LFB7fTRODWw9JbNcAPF0k6k_RcSeMh6_79wQ9X13-bW6y2cP1bTOdZYJXNGSKdoR0E1Z3wJRQqpoD4-lTirxUigpezInKJ7IsuKy5mlNeAiMly-tCka7igp-gs11u2uDfBnxoe-0lGCMsuI1vKaFFUXJa5Yn-3FE5OO8H6Nr1oHsxxITabTXtoZpkv-9jN_Me1EH-7yKBHzsgpG9XbjPYdOUHQW8JCJdI</recordid><startdate>20120524</startdate><enddate>20120524</enddate><creator>Zheng, Suqing</creator><creator>Santosh Laxmi, Y. 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R ; David, Emilie ; Dinkova-Kostova, Albena T ; Shiavoni, Katherine H ; Ren, Yanqing ; Zheng, Ying ; Trevino, Isaac ; Bumeister, Ronald ; Ojima, Iwao ; Wigley, W. Christian ; Bliska, James B ; Mierke, Dale F ; Honda, Tadashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-d1f00f529fe2dadd8be23520647dd1a36b0d45c763c93db137e2072496d0f83a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alkynes - chemical synthesis</topic><topic>Alkynes - chemistry</topic><topic>Alkynes - pharmacology</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemistry</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Anticarcinogenic Agents - chemical synthesis</topic><topic>Anticarcinogenic Agents - chemistry</topic><topic>Anticarcinogenic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cytoprotection</topic><topic>I-kappa B Kinase - antagonists & inhibitors</topic><topic>Interleukin-1beta - metabolism</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages - cytology</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Mice</topic><topic>NAD(P)H Dehydrogenase (Quinone) - biosynthesis</topic><topic>Nitric Oxide - antagonists & inhibitors</topic><topic>Nitric Oxide - biosynthesis</topic><topic>Nitriles - chemical synthesis</topic><topic>Nitriles - chemistry</topic><topic>Nitriles - pharmacology</topic><topic>Oleanolic Acid - analogs & derivatives</topic><topic>Oleanolic Acid - chemistry</topic><topic>Oleanolic Acid - pharmacology</topic><topic>Phenanthrenes - chemistry</topic><topic>Phenanthrenes - pharmacology</topic><topic>Thiophenes - chemistry</topic><topic>Thiophenes - pharmacology</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Suqing</creatorcontrib><creatorcontrib>Santosh Laxmi, Y. 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Christian</au><au>Bliska, James B</au><au>Mierke, Dale F</au><au>Honda, Tadashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-05-24</date><risdate>2012</risdate><volume>55</volume><issue>10</issue><spage>4837</spage><epage>4846</epage><pages>4837-4846</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22533790</pmid><doi>10.1021/jm3003922</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2012-05, Vol.55 (10), p.4837-4846 |
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| source | ACS Publications; MEDLINE |
| subjects | Alkynes - chemical synthesis Alkynes - chemistry Alkynes - pharmacology Amides - chemistry Amides - pharmacology Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anticarcinogenic Agents - chemical synthesis Anticarcinogenic Agents - chemistry Anticarcinogenic Agents - pharmacology Apoptosis - drug effects Cell Line Cell Line, Tumor Cytoprotection I-kappa B Kinase - antagonists & inhibitors Interleukin-1beta - metabolism Lipopolysaccharides - pharmacology Macrophages - cytology Macrophages - drug effects Macrophages - metabolism Mice NAD(P)H Dehydrogenase (Quinone) - biosynthesis Nitric Oxide - antagonists & inhibitors Nitric Oxide - biosynthesis Nitriles - chemical synthesis Nitriles - chemistry Nitriles - pharmacology Oleanolic Acid - analogs & derivatives Oleanolic Acid - chemistry Oleanolic Acid - pharmacology Phenanthrenes - chemistry Phenanthrenes - pharmacology Thiophenes - chemistry Thiophenes - pharmacology Tumor Necrosis Factor-alpha - metabolism |
| title | Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents |
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