Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2- a]benzimidazoles
A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2- a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure–activity relationships (SAR) for the this activity, either dire...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2011-07, Vol.19 (13), p.4091-4100 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Lyons, Dani M. Huttunen, Kristiina M. Browne, Kylie A. Ciccone, Annette Trapani, Joseph A. Denny, William A. Spicer, Julie A. |
| description | A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-
a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure–activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors. |
| doi_str_mv | 10.1016/j.bmc.2011.05.013 |
| format | Article |
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a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure–activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors.</description><subject>Antineoplastic agents</subject><subject>benzimidazole</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - toxicity</subject><subject>Biological and medical sciences</subject><subject>blood serum</subject><subject>Cell Line</subject><subject>Dicyanopyrido[1,2- a]benzimidazole</subject><subject>General aspects</subject><subject>Humans</subject><subject>Killer Cells, Natural - drug effects</subject><subject>Medical sciences</subject><subject>natural killer cells</subject><subject>Perforin</subject><subject>Perforin - antagonists & inhibitors</subject><subject>Perforin - metabolism</subject><subject>Perforin inhibitor</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtv1DAURi0EokPhB7CBbBCbJlw_46grVPGoVIkFdIWQZTs29SixBztBmv56PJop7FjdxT3ffRyEXmLoMGDxbtuZ2XYEMO6Ad4DpI7TBTLCW0gE_RhsYhGxBDuIMPStlCwCEDfgpOiNYCCYJ2yBzHe-CCUtIsUm-We5cY900rZPOjV-jfWjsXPYph9iYfYNbPYeYWnLB2jHYvY5pt89hTN_xBWkb_cO4eB_mMOr7NLnyHD3xeiruxameo9uPH75dfW5vvny6vnp_01pG5dJSAAFc9LL3ErywBGsyUOG5IAzLEYBRL6itiOCOGcyM8dYTyXrLBTeEnqO3x7m7nH6trixqDuXwjI4urUXJXhDKeugriY-kzamU7Lza5TDrvFcY1MGs2qpqVh3MKuCqmq2ZV6fpq5nd-DfxoLICb06ALlZPPutoQ_nHMQoE2OHM10fO66T0z1yZ2691EwfAMHCJK3F5JFy19Tu4rIoNLlo3huzsosYU_nPoH6zInSA</recordid><startdate>20110701</startdate><enddate>20110701</enddate><creator>Lyons, Dani M.</creator><creator>Huttunen, Kristiina M.</creator><creator>Browne, Kylie A.</creator><creator>Ciccone, Annette</creator><creator>Trapani, Joseph A.</creator><creator>Denny, William A.</creator><creator>Spicer, Julie A.</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>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20110701</creationdate><title>Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2- a]benzimidazoles</title><author>Lyons, Dani M. ; Huttunen, Kristiina M. ; Browne, Kylie A. ; Ciccone, Annette ; Trapani, Joseph A. ; Denny, William A. ; Spicer, Julie A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-3006056787f80f6c21a2936f562418d0043f63c05665e4b14bbfcf2847c565b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Antineoplastic agents</topic><topic>benzimidazole</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - toxicity</topic><topic>Biological and medical sciences</topic><topic>blood serum</topic><topic>Cell Line</topic><topic>Dicyanopyrido[1,2- a]benzimidazole</topic><topic>General aspects</topic><topic>Humans</topic><topic>Killer Cells, Natural - drug effects</topic><topic>Medical sciences</topic><topic>natural killer cells</topic><topic>Perforin</topic><topic>Perforin - antagonists & inhibitors</topic><topic>Perforin - metabolism</topic><topic>Perforin inhibitor</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lyons, Dani M.</creatorcontrib><creatorcontrib>Huttunen, Kristiina M.</creatorcontrib><creatorcontrib>Browne, Kylie A.</creatorcontrib><creatorcontrib>Ciccone, Annette</creatorcontrib><creatorcontrib>Trapani, Joseph A.</creatorcontrib><creatorcontrib>Denny, William A.</creatorcontrib><creatorcontrib>Spicer, Julie A.</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lyons, Dani M.</au><au>Huttunen, Kristiina M.</au><au>Browne, Kylie A.</au><au>Ciccone, Annette</au><au>Trapani, Joseph A.</au><au>Denny, William A.</au><au>Spicer, Julie A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2- a]benzimidazoles</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2011-07-01</date><risdate>2011</risdate><volume>19</volume><issue>13</issue><spage>4091</spage><epage>4100</epage><pages>4091-4100</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-
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| issn | 0968-0896 1464-3391 |
| language | eng |
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| subjects | Antineoplastic agents benzimidazole Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - toxicity Biological and medical sciences blood serum Cell Line Dicyanopyrido[1,2- a]benzimidazole General aspects Humans Killer Cells, Natural - drug effects Medical sciences natural killer cells Perforin Perforin - antagonists & inhibitors Perforin - metabolism Perforin inhibitor Pharmacology. Drug treatments Structure-Activity Relationship structure-activity relationships |
| title | Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2- a]benzimidazoles |
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