Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors
[Display omitted] Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA)...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2018-02, Vol.26 (3), p.775-785 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Ota, Yosuke Miyamura, Shin Araki, Misaho Itoh, Yukihiro Yasuda, Shusuke Masuda, Mitsuharu Taniguchi, Tomoyuki Sowa, Yoshihiro Sakai, Toshiyuki Itami, Kenichiro Yamaguchi, Junichiro Suzuki, Takayoshi |
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Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors. |
| doi_str_mv | 10.1016/j.bmc.2017.12.045 |
| format | Article |
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Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2017.12.045</identifier><identifier>PMID: 29331452</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Catalytic Domain ; Cell Cycle Checkpoints - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cyclopropanes - chemical synthesis ; Cyclopropanes - chemistry ; Cyclopropanes - pharmacology ; Drug Design ; Enzyme Assays ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Fukuyama amine synthesis ; Histone Demethylases - antagonists & inhibitors ; Histone Demethylases - metabolism ; Humans ; Inhibitor ; Lysine-specific demethylase 1 (LSD1) ; Monoamine Oxidase - chemistry ; Monoamine Oxidase - metabolism ; Structure-activity relationship (SAR) study ; γ-Turn mimetics</subject><ispartof>Bioorganic & medicinal chemistry, 2018-02, Vol.26 (3), p.775-785</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-e682aa4e138e6b724c1f91544ddde1455910286ffc01114f424601b98ba727143</citedby><cites>FETCH-LOGICAL-c396t-e682aa4e138e6b724c1f91544ddde1455910286ffc01114f424601b98ba727143</cites><orcidid>0000-0002-3410-2924</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2017.12.045$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29331452$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ota, Yosuke</creatorcontrib><creatorcontrib>Miyamura, Shin</creatorcontrib><creatorcontrib>Araki, Misaho</creatorcontrib><creatorcontrib>Itoh, Yukihiro</creatorcontrib><creatorcontrib>Yasuda, Shusuke</creatorcontrib><creatorcontrib>Masuda, Mitsuharu</creatorcontrib><creatorcontrib>Taniguchi, Tomoyuki</creatorcontrib><creatorcontrib>Sowa, Yoshihiro</creatorcontrib><creatorcontrib>Sakai, Toshiyuki</creatorcontrib><creatorcontrib>Itami, Kenichiro</creatorcontrib><creatorcontrib>Yamaguchi, Junichiro</creatorcontrib><creatorcontrib>Suzuki, Takayoshi</creatorcontrib><title>Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Catalytic Domain</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cyclopropanes - chemical synthesis</subject><subject>Cyclopropanes - chemistry</subject><subject>Cyclopropanes - pharmacology</subject><subject>Drug Design</subject><subject>Enzyme Assays</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fukuyama amine synthesis</subject><subject>Histone Demethylases - antagonists & inhibitors</subject><subject>Histone Demethylases - metabolism</subject><subject>Humans</subject><subject>Inhibitor</subject><subject>Lysine-specific demethylase 1 (LSD1)</subject><subject>Monoamine Oxidase - chemistry</subject><subject>Monoamine Oxidase - metabolism</subject><subject>Structure-activity relationship (SAR) study</subject><subject>γ-Turn mimetics</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EgvL4ADYoSxYkeBzHtcUKladUCSFgbTnOhLrKA-ykEt_Ff_BNuCqwZDWzOPdq5hByDDQDCuJ8mZWtzRiFaQYso7zYIhPggqd5rmCbTKgSMqVSiT2yH8KSUsq4gl2yx1SeAy_YhDxeYXCv3VkSPrphEfeQmK5KcGWa0Qyu75K-Tr4-02H0XdK6FgdnIxKS-dMVpAEbtINbYeK6hSvd0PtwSHZq0wQ8-pkH5OXm-nl2l84fbu9nl_PU5koMKQrJjOEIuURRThm3UCsoOK-qCuNthQLKpKhrSwGA15xxQaFUsjRTNgWeH5DTTe-b799HDINuXbDYNKbDfgwalFSF5LJQEYUNan0fgsdav3nXGv-hgeq1Sb3U0aRem9TAdDQZMyc_9WPZYvWX-FUXgYsNgPHJlUOvg3XYWaycj1J01bt_6r8B_eWDKg</recordid><startdate>20180201</startdate><enddate>20180201</enddate><creator>Ota, Yosuke</creator><creator>Miyamura, Shin</creator><creator>Araki, Misaho</creator><creator>Itoh, Yukihiro</creator><creator>Yasuda, Shusuke</creator><creator>Masuda, Mitsuharu</creator><creator>Taniguchi, Tomoyuki</creator><creator>Sowa, Yoshihiro</creator><creator>Sakai, Toshiyuki</creator><creator>Itami, Kenichiro</creator><creator>Yamaguchi, Junichiro</creator><creator>Suzuki, Takayoshi</creator><general>Elsevier Ltd</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><orcidid>https://orcid.org/0000-0002-3410-2924</orcidid></search><sort><creationdate>20180201</creationdate><title>Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors</title><author>Ota, Yosuke ; Miyamura, Shin ; Araki, Misaho ; Itoh, Yukihiro ; Yasuda, Shusuke ; Masuda, Mitsuharu ; Taniguchi, Tomoyuki ; Sowa, Yoshihiro ; Sakai, Toshiyuki ; Itami, Kenichiro ; Yamaguchi, Junichiro ; Suzuki, Takayoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-e682aa4e138e6b724c1f91544ddde1455910286ffc01114f424601b98ba727143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Catalytic Domain</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cyclopropanes - chemical synthesis</topic><topic>Cyclopropanes - chemistry</topic><topic>Cyclopropanes - pharmacology</topic><topic>Drug Design</topic><topic>Enzyme Assays</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fukuyama amine synthesis</topic><topic>Histone Demethylases - antagonists & inhibitors</topic><topic>Histone Demethylases - metabolism</topic><topic>Humans</topic><topic>Inhibitor</topic><topic>Lysine-specific demethylase 1 (LSD1)</topic><topic>Monoamine Oxidase - chemistry</topic><topic>Monoamine Oxidase - metabolism</topic><topic>Structure-activity relationship (SAR) study</topic><topic>γ-Turn mimetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ota, Yosuke</creatorcontrib><creatorcontrib>Miyamura, Shin</creatorcontrib><creatorcontrib>Araki, Misaho</creatorcontrib><creatorcontrib>Itoh, Yukihiro</creatorcontrib><creatorcontrib>Yasuda, Shusuke</creatorcontrib><creatorcontrib>Masuda, Mitsuharu</creatorcontrib><creatorcontrib>Taniguchi, Tomoyuki</creatorcontrib><creatorcontrib>Sowa, Yoshihiro</creatorcontrib><creatorcontrib>Sakai, Toshiyuki</creatorcontrib><creatorcontrib>Itami, Kenichiro</creatorcontrib><creatorcontrib>Yamaguchi, Junichiro</creatorcontrib><creatorcontrib>Suzuki, Takayoshi</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>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ota, Yosuke</au><au>Miyamura, Shin</au><au>Araki, Misaho</au><au>Itoh, Yukihiro</au><au>Yasuda, Shusuke</au><au>Masuda, Mitsuharu</au><au>Taniguchi, Tomoyuki</au><au>Sowa, Yoshihiro</au><au>Sakai, Toshiyuki</au><au>Itami, Kenichiro</au><au>Yamaguchi, Junichiro</au><au>Suzuki, Takayoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2018-02-01</date><risdate>2018</risdate><volume>26</volume><issue>3</issue><spage>775</spage><epage>785</epage><pages>775-785</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29331452</pmid><doi>10.1016/j.bmc.2017.12.045</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-3410-2924</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2018-02, Vol.26 (3), p.775-785 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Catalytic Domain Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cyclopropanes - chemical synthesis Cyclopropanes - chemistry Cyclopropanes - pharmacology Drug Design Enzyme Assays Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Fukuyama amine synthesis Histone Demethylases - antagonists & inhibitors Histone Demethylases - metabolism Humans Inhibitor Lysine-specific demethylase 1 (LSD1) Monoamine Oxidase - chemistry Monoamine Oxidase - metabolism Structure-activity relationship (SAR) study γ-Turn mimetics |
| title | Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors |
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