Synthesis, Resolution, and Biological Evaluation of Atropisomeric (aR)- and (aS)‑16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition
The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (C...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-09, Vol.56 (18), p.7289-7301 |
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| creator | Yoshida, Kenyu Itoyama, Ryosuke Yamahira, Masashi Tanaka, Junji Loaëc, Nadège Lozach, Olivier Durieu, Emilie Fukuda, Tsutomu Ishibashi, Fumito Meijer, Laurent Iwao, Masatomo |
| description | The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3α/β, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities. |
| doi_str_mv | 10.1021/jm400719y |
| format | Article |
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The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3α/β, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm400719y</identifier><identifier>PMID: 23981088</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Chemistry Techniques, Synthetic ; DNA Topoisomerases, Type I - chemistry ; DNA Topoisomerases, Type I - metabolism ; Humans ; Molecular Docking Simulation ; Polycyclic Compounds - chemical synthesis ; Polycyclic Compounds - chemistry ; Polycyclic Compounds - metabolism ; Polycyclic Compounds - pharmacology ; Protein Conformation ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein Kinases - chemistry ; Protein Kinases - metabolism ; Stereoisomerism ; Structure-Activity Relationship ; Substrate Specificity ; Topoisomerase I Inhibitors - chemical synthesis ; Topoisomerase I Inhibitors - chemistry ; Topoisomerase I Inhibitors - metabolism ; Topoisomerase I Inhibitors - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2013-09, Vol.56 (18), p.7289-7301</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-14d93a843e27291d4ea335c2056871f3672254b9c554697da64d73b573953b363</citedby><cites>FETCH-LOGICAL-a381t-14d93a843e27291d4ea335c2056871f3672254b9c554697da64d73b573953b363</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/jm400719y$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm400719y$$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/23981088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoshida, Kenyu</creatorcontrib><creatorcontrib>Itoyama, Ryosuke</creatorcontrib><creatorcontrib>Yamahira, Masashi</creatorcontrib><creatorcontrib>Tanaka, Junji</creatorcontrib><creatorcontrib>Loaëc, Nadège</creatorcontrib><creatorcontrib>Lozach, Olivier</creatorcontrib><creatorcontrib>Durieu, Emilie</creatorcontrib><creatorcontrib>Fukuda, Tsutomu</creatorcontrib><creatorcontrib>Ishibashi, Fumito</creatorcontrib><creatorcontrib>Meijer, Laurent</creatorcontrib><creatorcontrib>Iwao, Masatomo</creatorcontrib><title>Synthesis, Resolution, and Biological Evaluation of Atropisomeric (aR)- and (aS)‑16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3α/β, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Chemistry Techniques, Synthetic</subject><subject>DNA Topoisomerases, Type I - chemistry</subject><subject>DNA Topoisomerases, Type I - metabolism</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Polycyclic Compounds - chemical synthesis</subject><subject>Polycyclic Compounds - chemistry</subject><subject>Polycyclic Compounds - metabolism</subject><subject>Polycyclic Compounds - pharmacology</subject><subject>Protein Conformation</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinases - chemistry</subject><subject>Protein Kinases - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><subject>Topoisomerase I Inhibitors - chemical synthesis</subject><subject>Topoisomerase I Inhibitors - chemistry</subject><subject>Topoisomerase I Inhibitors - metabolism</subject><subject>Topoisomerase I Inhibitors - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1u1DAUhS0EokNhwQsgb5BmpKb4N066G0YDrSg_6tB15CQO45FjD7ZTkR2vwCPxKjxJnU7bFRtbuv58zj06ALzG6BQjgt_teoaQwOX4BMwwJyhjBWJPwQwhQjKSE3oEXoSwQwhRTOhzcERoWWBUFDPwdzPauFVBhxN4pYIzQ9TOnkBpW_heO-N-6EYauL6RZpDTE3QdXEbv9jq4XnndwLm8WmR3H-Zys_j3-w_Os88qbkdjZK_S4bUN8MsZvLb656DguutUE8MklJzh8pdOBqut9tLoOMJkMY03yiRK39yNOvjNu6i0hZ-0lUEFeGG3utbTQi_Bs06aoF7d38fg-sP6--o8u_z68WK1vMwkLXDMMGtLKgtGFRGkxC1TklLeEMTzQuCO5oIQzuqy4ZzlpWhlzlpBay5oyWlNc3oM5gfdvXcpRohVr0Mz5bPKDaHCjApeJD2R0MUBbbwLwauu2nvdSz9WGFVTY9VjY4l9cy871L1qH8mHihLw9gDIJlQ7N3ibUv5H6BZNIJ48</recordid><startdate>20130926</startdate><enddate>20130926</enddate><creator>Yoshida, Kenyu</creator><creator>Itoyama, Ryosuke</creator><creator>Yamahira, Masashi</creator><creator>Tanaka, Junji</creator><creator>Loaëc, Nadège</creator><creator>Lozach, Olivier</creator><creator>Durieu, Emilie</creator><creator>Fukuda, Tsutomu</creator><creator>Ishibashi, Fumito</creator><creator>Meijer, Laurent</creator><creator>Iwao, Masatomo</creator><general>American Chemical Society</general><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>20130926</creationdate><title>Synthesis, Resolution, and Biological Evaluation of Atropisomeric (aR)- and (aS)‑16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition</title><author>Yoshida, Kenyu ; Itoyama, Ryosuke ; Yamahira, Masashi ; Tanaka, Junji ; Loaëc, Nadège ; Lozach, Olivier ; Durieu, Emilie ; Fukuda, Tsutomu ; Ishibashi, Fumito ; Meijer, Laurent ; Iwao, Masatomo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-14d93a843e27291d4ea335c2056871f3672254b9c554697da64d73b573953b363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Chemistry Techniques, Synthetic</topic><topic>DNA Topoisomerases, Type I - chemistry</topic><topic>DNA Topoisomerases, Type I - metabolism</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Polycyclic Compounds - chemical synthesis</topic><topic>Polycyclic Compounds - chemistry</topic><topic>Polycyclic Compounds - metabolism</topic><topic>Polycyclic Compounds - pharmacology</topic><topic>Protein Conformation</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinases - chemistry</topic><topic>Protein Kinases - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><topic>Topoisomerase I Inhibitors - chemical synthesis</topic><topic>Topoisomerase I Inhibitors - chemistry</topic><topic>Topoisomerase I Inhibitors - metabolism</topic><topic>Topoisomerase I Inhibitors - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoshida, Kenyu</creatorcontrib><creatorcontrib>Itoyama, Ryosuke</creatorcontrib><creatorcontrib>Yamahira, Masashi</creatorcontrib><creatorcontrib>Tanaka, Junji</creatorcontrib><creatorcontrib>Loaëc, Nadège</creatorcontrib><creatorcontrib>Lozach, Olivier</creatorcontrib><creatorcontrib>Durieu, Emilie</creatorcontrib><creatorcontrib>Fukuda, Tsutomu</creatorcontrib><creatorcontrib>Ishibashi, Fumito</creatorcontrib><creatorcontrib>Meijer, Laurent</creatorcontrib><creatorcontrib>Iwao, Masatomo</creatorcontrib><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>Yoshida, Kenyu</au><au>Itoyama, Ryosuke</au><au>Yamahira, Masashi</au><au>Tanaka, Junji</au><au>Loaëc, Nadège</au><au>Lozach, Olivier</au><au>Durieu, Emilie</au><au>Fukuda, Tsutomu</au><au>Ishibashi, Fumito</au><au>Meijer, Laurent</au><au>Iwao, Masatomo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Resolution, and Biological Evaluation of Atropisomeric (aR)- and (aS)‑16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-09-26</date><risdate>2013</risdate><volume>56</volume><issue>18</issue><spage>7289</spage><epage>7301</epage><pages>7289-7301</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3α/β, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23981088</pmid><doi>10.1021/jm400719y</doi><tpages>13</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Cell Line, Tumor Chemistry Techniques, Synthetic DNA Topoisomerases, Type I - chemistry DNA Topoisomerases, Type I - metabolism Humans Molecular Docking Simulation Polycyclic Compounds - chemical synthesis Polycyclic Compounds - chemistry Polycyclic Compounds - metabolism Polycyclic Compounds - pharmacology Protein Conformation Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Kinases - chemistry Protein Kinases - metabolism Stereoisomerism Structure-Activity Relationship Substrate Specificity Topoisomerase I Inhibitors - chemical synthesis Topoisomerase I Inhibitors - chemistry Topoisomerase I Inhibitors - metabolism Topoisomerase I Inhibitors - pharmacology |
| title | Synthesis, Resolution, and Biological Evaluation of Atropisomeric (aR)- and (aS)‑16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition |
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