Synthesis of novel 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases
The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6784-6788 |
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| creator | Deau, Emmanuel Loidreau, Yvonnick Marchand, Pascal Nourrisson, Marie-Renée Loaëc, Nadège Meijer, Laurent Levacher, Vincent Besson, Thierry |
| description | The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49nM and proved to be specific to CLK1 among the panel of tested kinases. |
| doi_str_mv | 10.1016/j.bmcl.2013.10.019 |
| format | Article |
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Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49nM and proved to be specific to CLK1 among the panel of tested kinases.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.10.019</identifier><identifier>PMID: 24176400</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Amines - chemical synthesis ; Amines - chemistry ; Amines - metabolism ; Amines - pharmacology ; Catalysis ; Chemical Sciences ; chemistry ; Cyclin-dependent kinase 5 ; Cyclization ; Dimroth rearrangement ; Enzyme Activation - drug effects ; Formamide degradation ; Heterocyclic Compounds, 3-Ring - chemical synthesis ; Heterocyclic Compounds, 3-Ring - chemistry ; Heterocyclic Compounds, 3-Ring - metabolism ; Heterocyclic Compounds, 3-Ring - pharmacology ; inhibitory concentration 50 ; microwave treatment ; Microwave-assisted chemistry ; Microwaves ; Organic chemistry ; Palladium - chemistry ; phosphotransferases (kinases) ; Protein Binding - drug effects ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Pyridines - chemistry ; Pyrimidines - chemistry ; Serine/threonine kinases inhibitors ; Structure-Activity Relationship ; Suzuki–Miyaura cross-coupling</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-12, Vol.23 (24), p.6784-6788</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. 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Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49nM and proved to be specific to CLK1 among the panel of tested kinases.</description><subject>Amines - chemical synthesis</subject><subject>Amines - chemistry</subject><subject>Amines - metabolism</subject><subject>Amines - pharmacology</subject><subject>Catalysis</subject><subject>Chemical Sciences</subject><subject>chemistry</subject><subject>Cyclin-dependent kinase 5</subject><subject>Cyclization</subject><subject>Dimroth rearrangement</subject><subject>Enzyme Activation - drug effects</subject><subject>Formamide degradation</subject><subject>Heterocyclic Compounds, 3-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, 3-Ring - chemistry</subject><subject>Heterocyclic Compounds, 3-Ring - metabolism</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>inhibitory concentration 50</subject><subject>microwave treatment</subject><subject>Microwave-assisted chemistry</subject><subject>Microwaves</subject><subject>Organic chemistry</subject><subject>Palladium - chemistry</subject><subject>phosphotransferases (kinases)</subject><subject>Protein Binding - drug effects</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Pyridines - chemistry</subject><subject>Pyrimidines - chemistry</subject><subject>Serine/threonine kinases inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Suzuki–Miyaura cross-coupling</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1uEzEQx1cIREvhBTjAHkHKpuO196viUlVAkSI4pJWQqsry2t5kwsYOtjdSbjxTH4knwasNPcLFY8385u8ZzyTJawJzAqQ838zbreznORAaHXMgzZPklLCSZZRB8TQ5haaErG7Y95PkhfcbAMKAsefJSc5IVTKA0-RheTBhrT361HapsXvdp1Xmh9YHDEPQKt0dHCp7l__-9TCj8bhgs-K-G5y9o7M8U_djfIsKTcYysUWjfSqMSqMouvRrJtyhjw7R29VwDOm96AcR0JrxzQlEs8YWg3WHVMiAewzxshJofEiX2p3frF36A43w2r9MnnWi9_rV0Z4lt58-3lxdZ4tvn79cXS4yyVgVMi1BFqoq67Yiioq2azrRqprSaKqm0KxTeVtSUYNoaNFqqUVeVJ2oaQu6KGp6lryfdNei57vYZGyFW4H8-nLBRx9A01Qshz2J7LuJ3Tn7M_YZ-Ba91H0vjLaD56QAqMo4KPg_GgfImobBWEE-odJZ753uHssgwMcV4Bs-rgAfV2D0xRWISW-O-kO71eox5e_MI_B2AjphuVg59Px2GRViiYTmFaki8WEidPzePWrHvURtpFbotAxcWfxXBX8AKw_PmA</recordid><startdate>20131215</startdate><enddate>20131215</enddate><creator>Deau, Emmanuel</creator><creator>Loidreau, Yvonnick</creator><creator>Marchand, Pascal</creator><creator>Nourrisson, Marie-Renée</creator><creator>Loaëc, Nadège</creator><creator>Meijer, Laurent</creator><creator>Levacher, Vincent</creator><creator>Besson, Thierry</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-3511-4916</orcidid><orcidid>https://orcid.org/0000-0003-3025-6659</orcidid><orcidid>https://orcid.org/0000-0001-7773-8642</orcidid><orcidid>https://orcid.org/0000-0002-6429-1965</orcidid><orcidid>https://orcid.org/0000-0001-5567-0210</orcidid></search><sort><creationdate>20131215</creationdate><title>Synthesis of novel 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases</title><author>Deau, Emmanuel ; 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Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49nM and proved to be specific to CLK1 among the panel of tested kinases.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24176400</pmid><doi>10.1016/j.bmcl.2013.10.019</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0003-3511-4916</orcidid><orcidid>https://orcid.org/0000-0003-3025-6659</orcidid><orcidid>https://orcid.org/0000-0001-7773-8642</orcidid><orcidid>https://orcid.org/0000-0002-6429-1965</orcidid><orcidid>https://orcid.org/0000-0001-5567-0210</orcidid></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry letters, 2013-12, Vol.23 (24), p.6784-6788 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Amines - chemical synthesis Amines - chemistry Amines - metabolism Amines - pharmacology Catalysis Chemical Sciences chemistry Cyclin-dependent kinase 5 Cyclization Dimroth rearrangement Enzyme Activation - drug effects Formamide degradation Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - metabolism Heterocyclic Compounds, 3-Ring - pharmacology inhibitory concentration 50 microwave treatment Microwave-assisted chemistry Microwaves Organic chemistry Palladium - chemistry phosphotransferases (kinases) Protein Binding - drug effects Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Pyridines - chemistry Pyrimidines - chemistry Serine/threonine kinases inhibitors Structure-Activity Relationship Suzuki–Miyaura cross-coupling |
| title | Synthesis of novel 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases |
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