Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia
Summary Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferat...
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| Veröffentlicht in: | Investigational new drugs 2020-02, Vol.38 (1), p.79-91 |
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| creator | Yang, Jincheng Chen, Kun Wang, Bin Wang, Liudi Qi, Shuya Wang, Weihua |
| description | Summary
Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); however, biological assays of NF-κB activity and NO-inhibition indicated that five selected compounds were TLR7 antagonists. Molecular docking indicated the binding mode differences: antagonists binding TLR7 in a different direction and interacting with adjacent TLR7 with difficulty in forming dimers. |
| doi_str_mv | 10.1007/s10637-019-00793-5 |
| format | Article |
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Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); however, biological assays of NF-κB activity and NO-inhibition indicated that five selected compounds were TLR7 antagonists. Molecular docking indicated the binding mode differences: antagonists binding TLR7 in a different direction and interacting with adjacent TLR7 with difficulty in forming dimers.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-019-00793-5</identifier><identifier>PMID: 31270708</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Alopecia ; Alopecia - chemically induced ; Alopecia - drug therapy ; Alopecia - pathology ; Animals ; Antagonists ; Anti-Inflammatory Agents - chemical synthesis ; Anti-Inflammatory Agents - pharmacology ; Antineoplastic Agents - adverse effects ; Apoptosis ; Binding ; Biological activity ; Cell Proliferation ; Cells, Cultured ; Chain branching ; Chemotherapy ; Crystallization ; Cytokines - metabolism ; Dimers ; Drug Design ; Hair ; Hair loss ; Humans ; Imiquimod ; Immune system ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Molecular docking ; Molecular Docking Simulation ; Neoplasms - drug therapy ; Neoplasms - pathology ; NF-κB protein ; Oncology ; Pharmacology/Toxicology ; Preclinical Studies ; Proteins ; Quinoline ; Quinolines - chemistry ; Receptors ; Signal Transduction ; Stem cells ; Studies ; TLR7 protein ; Toll-Like Receptor 7 - antagonists & inhibitors ; Toll-like receptors ; Triazoles</subject><ispartof>Investigational new drugs, 2020-02, Vol.38 (1), p.79-91</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2019</rights><rights>Investigational New Drugs is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-1a9cd784375bd80d465de090e35c4e0f7fa9863dd39ddd5fe544e3fac0e4530a3</citedby><cites>FETCH-LOGICAL-c375t-1a9cd784375bd80d465de090e35c4e0f7fa9863dd39ddd5fe544e3fac0e4530a3</cites><orcidid>0000-0001-8453-8614</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-019-00793-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-019-00793-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27926,27927,41490,42559,51321</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31270708$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Jincheng</creatorcontrib><creatorcontrib>Chen, Kun</creatorcontrib><creatorcontrib>Wang, Bin</creatorcontrib><creatorcontrib>Wang, Liudi</creatorcontrib><creatorcontrib>Qi, Shuya</creatorcontrib><creatorcontrib>Wang, Weihua</creatorcontrib><title>Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); however, biological assays of NF-κB activity and NO-inhibition indicated that five selected compounds were TLR7 antagonists. Molecular docking indicated the binding mode differences: antagonists binding TLR7 in a different direction and interacting with adjacent TLR7 with difficulty in forming dimers.</description><subject>Alopecia</subject><subject>Alopecia - chemically induced</subject><subject>Alopecia - drug therapy</subject><subject>Alopecia - pathology</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Apoptosis</subject><subject>Binding</subject><subject>Biological activity</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Chain branching</subject><subject>Chemotherapy</subject><subject>Crystallization</subject><subject>Cytokines - metabolism</subject><subject>Dimers</subject><subject>Drug Design</subject><subject>Hair</subject><subject>Hair loss</subject><subject>Humans</subject><subject>Imiquimod</subject><subject>Immune system</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular docking</subject><subject>Molecular Docking Simulation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>NF-κB protein</subject><subject>Oncology</subject><subject>Pharmacology/Toxicology</subject><subject>Preclinical Studies</subject><subject>Proteins</subject><subject>Quinoline</subject><subject>Quinolines - chemistry</subject><subject>Receptors</subject><subject>Signal Transduction</subject><subject>Stem cells</subject><subject>Studies</subject><subject>TLR7 protein</subject><subject>Toll-Like Receptor 7 - antagonists & inhibitors</subject><subject>Toll-like receptors</subject><subject>Triazoles</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp9kE1LAzEQhoMotlb_gAcJeG100iSb5ih-Q0GQeg5pkm23tJs12RX23xtt1ZunmWGeeQcehM4pXFEAeZ0oFEwSoIrkUTEiDtCQCskIFLw4REOghSSFUnKATlJaAwBTkh-jAaMTCRKmQ-TufKqW9Rinvm5XuU9jbGqHF1XYhGVlzQYb21YfVdvjUOL57FWShUneYRu2Tehql3AZIrYrvw05IJqmJ1XtOpsRswmNt5U5RUel2SR_tq8j9PZwP799IrOXx-fbmxmxTIqWUKOsk1Oeh4WbguOFcB4UeCYs91DK0qhpwZxjyjknSi8496w0FjwXDAwboctdbhPDe-dTq9ehi3V-qScTQXmhhIBMTXaUjSGl6EvdxGprYq8p6C-xeidWZ7H6W6wW-ehiH90ttt79nvyYzADbASmv6qWPf7__if0Eb0KEYw</recordid><startdate>20200201</startdate><enddate>20200201</enddate><creator>Yang, Jincheng</creator><creator>Chen, Kun</creator><creator>Wang, Bin</creator><creator>Wang, Liudi</creator><creator>Qi, Shuya</creator><creator>Wang, Weihua</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7QO</scope><scope>7RV</scope><scope>7WY</scope><scope>7WZ</scope><scope>7X7</scope><scope>7XB</scope><scope>87Z</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8FL</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BEZIV</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FRNLG</scope><scope>FYUFA</scope><scope>F~G</scope><scope>GHDGH</scope><scope>K60</scope><scope>K6~</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>L.-</scope><scope>M0C</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQBIZ</scope><scope>PQBZA</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><orcidid>https://orcid.org/0000-0001-8453-8614</orcidid></search><sort><creationdate>20200201</creationdate><title>Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia</title><author>Yang, Jincheng ; Chen, Kun ; Wang, Bin ; Wang, Liudi ; Qi, Shuya ; Wang, Weihua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-1a9cd784375bd80d465de090e35c4e0f7fa9863dd39ddd5fe544e3fac0e4530a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Alopecia</topic><topic>Alopecia - chemically induced</topic><topic>Alopecia - drug therapy</topic><topic>Alopecia - pathology</topic><topic>Animals</topic><topic>Antagonists</topic><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Apoptosis</topic><topic>Binding</topic><topic>Biological activity</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Chain branching</topic><topic>Chemotherapy</topic><topic>Crystallization</topic><topic>Cytokines - metabolism</topic><topic>Dimers</topic><topic>Drug Design</topic><topic>Hair</topic><topic>Hair loss</topic><topic>Humans</topic><topic>Imiquimod</topic><topic>Immune system</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Molecular docking</topic><topic>Molecular Docking Simulation</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>NF-κB protein</topic><topic>Oncology</topic><topic>Pharmacology/Toxicology</topic><topic>Preclinical Studies</topic><topic>Proteins</topic><topic>Quinoline</topic><topic>Quinolines - chemistry</topic><topic>Receptors</topic><topic>Signal Transduction</topic><topic>Stem cells</topic><topic>Studies</topic><topic>TLR7 protein</topic><topic>Toll-Like Receptor 7 - antagonists & inhibitors</topic><topic>Toll-like receptors</topic><topic>Triazoles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Jincheng</creatorcontrib><creatorcontrib>Chen, Kun</creatorcontrib><creatorcontrib>Wang, Bin</creatorcontrib><creatorcontrib>Wang, Liudi</creatorcontrib><creatorcontrib>Qi, Shuya</creatorcontrib><creatorcontrib>Wang, Weihua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>ABI/INFORM Collection</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Business Premium Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Business Premium Collection (Alumni)</collection><collection>Health Research Premium Collection</collection><collection>ABI/INFORM Global (Corporate)</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Business Collection (Alumni Edition)</collection><collection>ProQuest Business Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM Global</collection><collection>ProQuest Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Business</collection><collection>ProQuest One Business (Alumni)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Jincheng</au><au>Chen, Kun</au><au>Wang, Bin</au><au>Wang, Liudi</au><au>Qi, Shuya</au><au>Wang, Weihua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2020-02-01</date><risdate>2020</risdate><volume>38</volume><issue>1</issue><spage>79</spage><epage>91</epage><pages>79-91</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); however, biological assays of NF-κB activity and NO-inhibition indicated that five selected compounds were TLR7 antagonists. Molecular docking indicated the binding mode differences: antagonists binding TLR7 in a different direction and interacting with adjacent TLR7 with difficulty in forming dimers.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>31270708</pmid><doi>10.1007/s10637-019-00793-5</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-8453-8614</orcidid></addata></record> |
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| subjects | Alopecia Alopecia - chemically induced Alopecia - drug therapy Alopecia - pathology Animals Antagonists Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - pharmacology Antineoplastic Agents - adverse effects Apoptosis Binding Biological activity Cell Proliferation Cells, Cultured Chain branching Chemotherapy Crystallization Cytokines - metabolism Dimers Drug Design Hair Hair loss Humans Imiquimod Immune system Medicine Medicine & Public Health Mice Mice, Inbred BALB C Molecular docking Molecular Docking Simulation Neoplasms - drug therapy Neoplasms - pathology NF-κB protein Oncology Pharmacology/Toxicology Preclinical Studies Proteins Quinoline Quinolines - chemistry Receptors Signal Transduction Stem cells Studies TLR7 protein Toll-Like Receptor 7 - antagonists & inhibitors Toll-like receptors Triazoles |
| title | Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia |
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