A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors
The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the mos...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-08, Vol.56 (15), p.6234-6247 |
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| container_issue | 15 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 56 |
| creator | Gucký, Tomáš Jorda, Radek Zatloukal, Marek Bazgier, Václav Berka, Karel Řezníčková, Eva Béres, Tibor Strnad, Miroslav Kryštof, Vladimír |
| description | The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety. |
| doi_str_mv | 10.1021/jm4006884 |
| format | Article |
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We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm4006884</identifier><identifier>PMID: 23829517</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adenine - analogs & derivatives ; Adenine - chemical synthesis ; Adenine - chemistry ; Adenine - pharmacology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; CDC2 Protein Kinase - antagonists & inhibitors ; Cell Line, Tumor ; Computer Simulation ; Cyclin-Dependent Kinase 2 - antagonists & inhibitors ; Cyclin-Dependent Kinases - antagonists & inhibitors ; Cyclopentanes - chemical synthesis ; Cyclopentanes - chemistry ; Cyclopentanes - pharmacology ; Drug Screening Assays, Antitumor ; Humans ; Methylamines - chemical synthesis ; Methylamines - chemistry ; Methylamines - pharmacology ; Models, Molecular ; Phosphorylation ; Purines - chemical synthesis ; Purines - chemistry ; Purines - pharmacology ; Retinoblastoma Protein - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2013-08, Vol.56 (15), p.6234-6247</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-90e3aa14ba2e47d66077dff0c2d27e81efea754ab19ccd1f170f670783600cb93</citedby><cites>FETCH-LOGICAL-a315t-90e3aa14ba2e47d66077dff0c2d27e81efea754ab19ccd1f170f670783600cb93</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/jm4006884$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm4006884$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,778,782,2754,27059,27907,27908,56721,56771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23829517$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gucký, Tomáš</creatorcontrib><creatorcontrib>Jorda, Radek</creatorcontrib><creatorcontrib>Zatloukal, Marek</creatorcontrib><creatorcontrib>Bazgier, Václav</creatorcontrib><creatorcontrib>Berka, Karel</creatorcontrib><creatorcontrib>Řezníčková, Eva</creatorcontrib><creatorcontrib>Béres, Tibor</creatorcontrib><creatorcontrib>Strnad, Miroslav</creatorcontrib><creatorcontrib>Kryštof, Vladimír</creatorcontrib><title>A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - chemical synthesis</subject><subject>Adenine - chemistry</subject><subject>Adenine - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>CDC2 Protein Kinase - antagonists & inhibitors</subject><subject>Cell Line, Tumor</subject><subject>Computer Simulation</subject><subject>Cyclin-Dependent Kinase 2 - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Cyclopentanes - chemical synthesis</subject><subject>Cyclopentanes - chemistry</subject><subject>Cyclopentanes - pharmacology</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Methylamines - chemical synthesis</subject><subject>Methylamines - chemistry</subject><subject>Methylamines - pharmacology</subject><subject>Models, Molecular</subject><subject>Phosphorylation</subject><subject>Purines - chemical synthesis</subject><subject>Purines - chemistry</subject><subject>Purines - pharmacology</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>Structure-Activity Relationship</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>eNpt0EtLw0AUhuFBFFurC_-AzEZQaPTMTJJJlqVeWixasG4Nk8mJnZJLnUmE_ntTWrtydTYPH5yXkEsGdww4u1-VPkAYRf4R6bOAg-dH4B-TPgDnHg-56JEz51YAIBgXp6THRcTjgMk--RzR1_oHC_qO1qCjdU4n5mtZbOi8brBqKB-Gw9hbWOPa1DWmaRvM6Ly1pkI63ujCVN4DrrHKtvjFVMohnVZLk5qmtu6cnOSqcHixvwPy8fS4GE-82dvzdDyaeUqwoPFiQKEU81PF0ZdZGIKUWZ6D5hmXGDHMUcnAVymLtc5YziTkoQQZiRBAp7EYkJvd7trW3y26JimN01gUqsK6dQnzWSxEHEno6O2Oals7ZzFP1taUym4SBsk2Z3LI2dmr_Wyblpgd5F-_DlzvgNIuWdWtrbov_xn6BZKden0</recordid><startdate>20130808</startdate><enddate>20130808</enddate><creator>Gucký, Tomáš</creator><creator>Jorda, Radek</creator><creator>Zatloukal, Marek</creator><creator>Bazgier, Václav</creator><creator>Berka, Karel</creator><creator>Řezníčková, Eva</creator><creator>Béres, Tibor</creator><creator>Strnad, Miroslav</creator><creator>Kryštof, Vladimír</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>20130808</creationdate><title>A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors</title><author>Gucký, Tomáš ; Jorda, Radek ; Zatloukal, Marek ; Bazgier, Václav ; Berka, Karel ; Řezníčková, Eva ; Béres, Tibor ; Strnad, Miroslav ; Kryštof, Vladimír</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-90e3aa14ba2e47d66077dff0c2d27e81efea754ab19ccd1f170f670783600cb93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - chemical synthesis</topic><topic>Adenine - chemistry</topic><topic>Adenine - pharmacology</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>CDC2 Protein Kinase - antagonists & inhibitors</topic><topic>Cell Line, Tumor</topic><topic>Computer Simulation</topic><topic>Cyclin-Dependent Kinase 2 - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Cyclopentanes - chemical synthesis</topic><topic>Cyclopentanes - chemistry</topic><topic>Cyclopentanes - pharmacology</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Methylamines - chemical synthesis</topic><topic>Methylamines - chemistry</topic><topic>Methylamines - pharmacology</topic><topic>Models, Molecular</topic><topic>Phosphorylation</topic><topic>Purines - chemical synthesis</topic><topic>Purines - chemistry</topic><topic>Purines - pharmacology</topic><topic>Retinoblastoma Protein - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gucký, Tomáš</creatorcontrib><creatorcontrib>Jorda, Radek</creatorcontrib><creatorcontrib>Zatloukal, Marek</creatorcontrib><creatorcontrib>Bazgier, Václav</creatorcontrib><creatorcontrib>Berka, Karel</creatorcontrib><creatorcontrib>Řezníčková, Eva</creatorcontrib><creatorcontrib>Béres, Tibor</creatorcontrib><creatorcontrib>Strnad, Miroslav</creatorcontrib><creatorcontrib>Kryštof, Vladimír</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>Gucký, Tomáš</au><au>Jorda, Radek</au><au>Zatloukal, Marek</au><au>Bazgier, Václav</au><au>Berka, Karel</au><au>Řezníčková, Eva</au><au>Béres, Tibor</au><au>Strnad, Miroslav</au><au>Kryštof, Vladimír</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-08-08</date><risdate>2013</risdate><volume>56</volume><issue>15</issue><spage>6234</spage><epage>6247</epage><pages>6234-6247</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23829517</pmid><doi>10.1021/jm4006884</doi><tpages>14</tpages></addata></record> |
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| subjects | Adenine - analogs & derivatives Adenine - chemical synthesis Adenine - chemistry Adenine - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis CDC2 Protein Kinase - antagonists & inhibitors Cell Line, Tumor Computer Simulation Cyclin-Dependent Kinase 2 - antagonists & inhibitors Cyclin-Dependent Kinases - antagonists & inhibitors Cyclopentanes - chemical synthesis Cyclopentanes - chemistry Cyclopentanes - pharmacology Drug Screening Assays, Antitumor Humans Methylamines - chemical synthesis Methylamines - chemistry Methylamines - pharmacology Models, Molecular Phosphorylation Purines - chemical synthesis Purines - chemistry Purines - pharmacology Retinoblastoma Protein - metabolism Structure-Activity Relationship |
| title | A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors |
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