Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents
SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting t...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (3), p.1469-1474 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Ishii, Hideki Koyama, Hiroko Hagiwara, Kyoji Miura, Tomoyuki Xue, Guangai Hashimoto, Yoshie Kitahara, Genta Aida, Yoko Suzuki, Masaaki |
| description | SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40μM), stronger inhibition of nuclear import (0.5:1.3μM), and viral replication in HIV-1-infected TZM-bl cells (24.6:100μM), human peripheral blood mononuclear cells (PMBCs) (30.1μM: toxic). Different spectra of inhibitory activities against infected three healthy humans macrophages with high (donor A) and low (donor B and C) amounts of virus were also observed. Thus 16 showed 10-times stronger activity than 1 (16:1; 0.1:0.01 and >0.001μM). The comparison of the inhibition of viral p24 antigen production was clearly indicated that compound 16 is at least twofold more potent anti-viral activity than 1. Thus, structures and actions of deoxy analogs particularly 16 could provide valuable information for the development of a novel class of anti-HIV-1 agents. |
| doi_str_mv | 10.1016/j.bmcl.2011.06.066 |
| format | Article |
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The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40μM), stronger inhibition of nuclear import (0.5:1.3μM), and viral replication in HIV-1-infected TZM-bl cells (24.6:100μM), human peripheral blood mononuclear cells (PMBCs) (30.1μM: toxic). Different spectra of inhibitory activities against infected three healthy humans macrophages with high (donor A) and low (donor B and C) amounts of virus were also observed. Thus 16 showed 10-times stronger activity than 1 (16:1; 0.1:<1.0μM) in the case of A, while 16 and 1 showed comparable activities in the cases of B and C (>0.01 and >0.001μM). The comparison of the inhibition of viral p24 antigen production was clearly indicated that compound 16 is at least twofold more potent anti-viral activity than 1. Thus, structures and actions of deoxy analogs particularly 16 could provide valuable information for the development of a novel class of anti-HIV-1 agents.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.06.066</identifier><identifier>PMID: 22244940</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacology ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; antigens ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; antiviral properties ; Asymmetric synthesis ; Biological and medical sciences ; Cytotoxicity ; Exploration ; Hematoxylin ; Hematoxylin - chemical synthesis ; Hematoxylin - chemistry ; Hematoxylin - pharmacology ; HIV infections ; HIV-1 ; HIV-1 - drug effects ; Human immunodeficiency virus 1 ; Humans ; immunosuppression (physiological) ; Macrophages ; Medical sciences ; Molecular Structure ; mononuclear leukocytes ; Nuclear transport ; Oxygen - chemistry ; p24 protein ; Peripheral blood mononuclear cells ; Pharmacology. Drug treatments ; physiological transport ; Replication ; SAR ; virus replication ; viruses ; Vpr</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-02, Vol.22 (3), p.1469-1474</ispartof><rights>2011</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-9b1bf53bfcd27e1dadf29a4cdf07f27ac13b84c13f9da20013b0798de54cd9753</citedby><cites>FETCH-LOGICAL-c508t-9b1bf53bfcd27e1dadf29a4cdf07f27ac13b84c13f9da20013b0798de54cd9753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11008493$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25476109$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22244940$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishii, Hideki</creatorcontrib><creatorcontrib>Koyama, Hiroko</creatorcontrib><creatorcontrib>Hagiwara, Kyoji</creatorcontrib><creatorcontrib>Miura, Tomoyuki</creatorcontrib><creatorcontrib>Xue, Guangai</creatorcontrib><creatorcontrib>Hashimoto, Yoshie</creatorcontrib><creatorcontrib>Kitahara, Genta</creatorcontrib><creatorcontrib>Aida, Yoko</creatorcontrib><creatorcontrib>Suzuki, Masaaki</creatorcontrib><title>Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40μM), stronger inhibition of nuclear import (0.5:1.3μM), and viral replication in HIV-1-infected TZM-bl cells (24.6:100μM), human peripheral blood mononuclear cells (PMBCs) (30.1μM: toxic). Different spectra of inhibitory activities against infected three healthy humans macrophages with high (donor A) and low (donor B and C) amounts of virus were also observed. Thus 16 showed 10-times stronger activity than 1 (16:1; 0.1:<1.0μM) in the case of A, while 16 and 1 showed comparable activities in the cases of B and C (>0.01 and >0.001μM). The comparison of the inhibition of viral p24 antigen production was clearly indicated that compound 16 is at least twofold more potent anti-viral activity than 1. Thus, structures and actions of deoxy analogs particularly 16 could provide valuable information for the development of a novel class of anti-HIV-1 agents.</description><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>antigens</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>antiviral properties</subject><subject>Asymmetric synthesis</subject><subject>Biological and medical sciences</subject><subject>Cytotoxicity</subject><subject>Exploration</subject><subject>Hematoxylin</subject><subject>Hematoxylin - chemical synthesis</subject><subject>Hematoxylin - chemistry</subject><subject>Hematoxylin - pharmacology</subject><subject>HIV infections</subject><subject>HIV-1</subject><subject>HIV-1 - drug effects</subject><subject>Human immunodeficiency virus 1</subject><subject>Humans</subject><subject>immunosuppression (physiological)</subject><subject>Macrophages</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>mononuclear leukocytes</subject><subject>Nuclear transport</subject><subject>Oxygen - chemistry</subject><subject>p24 protein</subject><subject>Peripheral blood mononuclear cells</subject><subject>Pharmacology. Drug treatments</subject><subject>physiological transport</subject><subject>Replication</subject><subject>SAR</subject><subject>virus replication</subject><subject>viruses</subject><subject>Vpr</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFvFCEUxonR2LX6D3jQuZj0MiswzMySeDGNtU2aeKg13ggDjy0bBirMTtz_3jfuqjeTL0Dg973H-wh5zeiaUda9362H0YQ1p4ytaYfqnpAVE52oG0Hbp2RFZUfrjRTfz8iLUnaUMkGFeE7OOOdCSEFXZHd3iNMDFF8qHW01-BTS1hsdKph12OvJp1glV1lIPw_1A4x6wkPwEW-yn_F9BrSiqphmCJUJupTFoePk6-ubbzWr9BbiVF6SZ06HAq9O-zm5v_r09fK6vv3y-eby421tWrqZajmwwbXN4IzlPTCrreNSC2Md7R3vtWHNsBG4Omk1x5magfZyY6FFRvZtc04ujnUfc_qxhzKp0RcDIegIaV8UZicYbXrZIcqPqMmplAxOPWY_6nxAaOE6tVNLxmrJWNEOtZjenOrvhxHsX8ufUBF4dwJ0wSRd1tH48o9rRd8xKpF7e-ScTkpvMzL3d9ipXYZq5e9WH44EYF6zh6yK8RANWJ_BTMom_7-f_gLDMqS3</recordid><startdate>20120201</startdate><enddate>20120201</enddate><creator>Ishii, Hideki</creator><creator>Koyama, Hiroko</creator><creator>Hagiwara, Kyoji</creator><creator>Miura, Tomoyuki</creator><creator>Xue, Guangai</creator><creator>Hashimoto, Yoshie</creator><creator>Kitahara, Genta</creator><creator>Aida, Yoko</creator><creator>Suzuki, Masaaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20120201</creationdate><title>Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents</title><author>Ishii, Hideki ; Koyama, Hiroko ; Hagiwara, Kyoji ; Miura, Tomoyuki ; Xue, Guangai ; Hashimoto, Yoshie ; Kitahara, Genta ; Aida, Yoko ; Suzuki, Masaaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-9b1bf53bfcd27e1dadf29a4cdf07f27ac13b84c13f9da20013b0798de54cd9753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Anti-HIV Agents - chemical synthesis</topic><topic>Anti-HIV Agents - chemistry</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>antigens</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>antiviral properties</topic><topic>Asymmetric synthesis</topic><topic>Biological and medical sciences</topic><topic>Cytotoxicity</topic><topic>Exploration</topic><topic>Hematoxylin</topic><topic>Hematoxylin - chemical synthesis</topic><topic>Hematoxylin - chemistry</topic><topic>Hematoxylin - pharmacology</topic><topic>HIV infections</topic><topic>HIV-1</topic><topic>HIV-1 - drug effects</topic><topic>Human immunodeficiency virus 1</topic><topic>Humans</topic><topic>immunosuppression (physiological)</topic><topic>Macrophages</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>mononuclear leukocytes</topic><topic>Nuclear transport</topic><topic>Oxygen - chemistry</topic><topic>p24 protein</topic><topic>Peripheral blood mononuclear cells</topic><topic>Pharmacology. Drug treatments</topic><topic>physiological transport</topic><topic>Replication</topic><topic>SAR</topic><topic>virus replication</topic><topic>viruses</topic><topic>Vpr</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishii, Hideki</creatorcontrib><creatorcontrib>Koyama, Hiroko</creatorcontrib><creatorcontrib>Hagiwara, Kyoji</creatorcontrib><creatorcontrib>Miura, Tomoyuki</creatorcontrib><creatorcontrib>Xue, Guangai</creatorcontrib><creatorcontrib>Hashimoto, Yoshie</creatorcontrib><creatorcontrib>Kitahara, Genta</creatorcontrib><creatorcontrib>Aida, Yoko</creatorcontrib><creatorcontrib>Suzuki, Masaaki</creatorcontrib><collection>AGRIS</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>Biotechnology Research Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishii, Hideki</au><au>Koyama, Hiroko</au><au>Hagiwara, Kyoji</au><au>Miura, Tomoyuki</au><au>Xue, Guangai</au><au>Hashimoto, Yoshie</au><au>Kitahara, Genta</au><au>Aida, Yoko</au><au>Suzuki, Masaaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-02-01</date><risdate>2012</risdate><volume>22</volume><issue>3</issue><spage>1469</spage><epage>1474</epage><pages>1469-1474</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40μM), stronger inhibition of nuclear import (0.5:1.3μM), and viral replication in HIV-1-infected TZM-bl cells (24.6:100μM), human peripheral blood mononuclear cells (PMBCs) (30.1μM: toxic). Different spectra of inhibitory activities against infected three healthy humans macrophages with high (donor A) and low (donor B and C) amounts of virus were also observed. Thus 16 showed 10-times stronger activity than 1 (16:1; 0.1:<1.0μM) in the case of A, while 16 and 1 showed comparable activities in the cases of B and C (>0.01 and >0.001μM). The comparison of the inhibition of viral p24 antigen production was clearly indicated that compound 16 is at least twofold more potent anti-viral activity than 1. Thus, structures and actions of deoxy analogs particularly 16 could provide valuable information for the development of a novel class of anti-HIV-1 agents.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22244940</pmid><doi>10.1016/j.bmcl.2011.06.066</doi><tpages>6</tpages></addata></record> |
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| subjects | Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents antigens Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology antiviral properties Asymmetric synthesis Biological and medical sciences Cytotoxicity Exploration Hematoxylin Hematoxylin - chemical synthesis Hematoxylin - chemistry Hematoxylin - pharmacology HIV infections HIV-1 HIV-1 - drug effects Human immunodeficiency virus 1 Humans immunosuppression (physiological) Macrophages Medical sciences Molecular Structure mononuclear leukocytes Nuclear transport Oxygen - chemistry p24 protein Peripheral blood mononuclear cells Pharmacology. Drug treatments physiological transport Replication SAR virus replication viruses Vpr |
| title | Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents |
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