Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors
PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coup...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2014-07, Vol.22 (14), p.3781-3790 |
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| container_issue | 14 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | O’Brien, Nathan J. Brzozowski, Martin Wilson, David J.D. Deady, Leslie W. Abbott, Belinda M. |
| description | PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed. |
| doi_str_mv | 10.1016/j.bmc.2014.04.037 |
| format | Article |
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Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. 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All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-ee3c3a6b4d20db95304869fec426c92b25cee3b169846ec28a337bb4f39a08e73</citedby><cites>FETCH-LOGICAL-c386t-ee3c3a6b4d20db95304869fec426c92b25cee3b169846ec28a337bb4f39a08e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089614003022$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24856302$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>O’Brien, Nathan J.</creatorcontrib><creatorcontrib>Brzozowski, Martin</creatorcontrib><creatorcontrib>Wilson, David J.D.</creatorcontrib><creatorcontrib>Deady, Leslie W.</creatorcontrib><creatorcontrib>Abbott, Belinda M.</creatorcontrib><title>Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed.</description><subject>3-Anilino-quinolin-2(1H)-ones</subject><subject>3-Phosphoinositide-dependent kinase 1 (PDK1)</subject><subject>3-Phosphoinositide-Dependent Protein Kinases</subject><subject>Aniline Compounds - chemical synthesis</subject><subject>Aniline Compounds - chemistry</subject><subject>Aniline Compounds - pharmacology</subject><subject>Buchwald–Hartwig cross-coupling</subject><subject>Cross-coupling</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Inhibitor</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Quinolones - chemical synthesis</subject><subject>Quinolones - chemistry</subject><subject>Quinolones - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU9LJDEQxYMoOs7uB_AifdRDxvybTIIn0V0VBRd29xySdLVm6Em0kx7w25th1KMIRVUdfvUo3kPoiJIZJVSeLWdu5WeMUDEjtfhiB02okAJzrukumhAtFSZKywN0mPOSEMKEpvvogAk1l5ywCfJ_X2N5ghxyY2PbuJD69Bi87RtY2360JaTYpK7Jo8sllLFA23BsY-hDTPhlrL1umJ3Qm1OcIlSZ3Py5uqNNiE_BhZKG_APtdbbP8PN9TtH_37_-Xd7g-4fr28uLe-y5kgUDcM-tdKJlpHV6zolQUnfgBZNeM8fmviKOSq2EBM-U5XzhnOi4tkTBgk_RyVb3eUgvI-RiViF76HsbIY3Z0LngWmvC5DdQLqUSasEqSreoH1LOA3TmeQgrO7waSswmBrM0NQazicGQWnzzyfG7_OhW0H5efPhegfMtANWPdYDBZB8gemjDAL6YNoUv5N8AHOSXeA</recordid><startdate>20140715</startdate><enddate>20140715</enddate><creator>O’Brien, Nathan J.</creator><creator>Brzozowski, Martin</creator><creator>Wilson, David J.D.</creator><creator>Deady, Leslie W.</creator><creator>Abbott, Belinda M.</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140715</creationdate><title>Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors</title><author>O’Brien, Nathan J. ; 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| ispartof | Bioorganic & medicinal chemistry, 2014-07, Vol.22 (14), p.3781-3790 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | 3-Anilino-quinolin-2(1H)-ones 3-Phosphoinositide-dependent kinase 1 (PDK1) 3-Phosphoinositide-Dependent Protein Kinases Aniline Compounds - chemical synthesis Aniline Compounds - chemistry Aniline Compounds - pharmacology Buchwald–Hartwig cross-coupling Cross-coupling Dose-Response Relationship, Drug Humans Inhibitor Models, Molecular Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Quinolones - chemical synthesis Quinolones - chemistry Quinolones - pharmacology Structure-Activity Relationship |
| title | Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors |
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