Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors
BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary in vitro activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed th...
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| Veröffentlicht in: | MedChemComm 2019-02, Vol.1 (2), p.294-299 |
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| creator | Li, Xinyu Shi, Binyu Teng, Yu Cheng, Yu Yang, Huizhu Li, Jiurong Wang, Lianjian He, Siying You, Qidong Xiang, Hua |
| description | BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary
in vitro
activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound
11g
displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC
50
= 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that
11g
inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that
11g
could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that
11g
was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. |
| doi_str_mv | 10.1039/c8md00413g |
| format | Article |
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in vitro
activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound
11g
displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC
50
= 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that
11g
inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that
11g
could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that
11g
was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases.</description><identifier>ISSN: 2040-2503</identifier><identifier>EISSN: 2040-2511</identifier><identifier>DOI: 10.1039/c8md00413g</identifier><identifier>PMID: 30881616</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Autoimmune diseases ; Bruton's tyrosine kinase ; Cell proliferation ; Derivatives ; Downstream effects ; Flow cytometry ; G1 phase ; Lead compounds ; Leukemia ; Lymphatic leukemia ; Lymphocytes B ; Medical treatment ; Optimization ; Phospholipase ; Phosphorylation ; Protein-tyrosine kinase ; Substrates ; Time dependence ; Tumors ; Tyrosine</subject><ispartof>MedChemComm, 2019-02, Vol.1 (2), p.294-299</ispartof><rights>Copyright Royal Society of Chemistry 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c373t-8ddae62c3fb1998e851109dd8ef689d5fb59c9950b7e64d0259cbbcdcbe6c4e73</citedby><cites>FETCH-LOGICAL-c373t-8ddae62c3fb1998e851109dd8ef689d5fb59c9950b7e64d0259cbbcdcbe6c4e73</cites><orcidid>0000-0002-8937-4062</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30881616$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Xinyu</creatorcontrib><creatorcontrib>Shi, Binyu</creatorcontrib><creatorcontrib>Teng, Yu</creatorcontrib><creatorcontrib>Cheng, Yu</creatorcontrib><creatorcontrib>Yang, Huizhu</creatorcontrib><creatorcontrib>Li, Jiurong</creatorcontrib><creatorcontrib>Wang, Lianjian</creatorcontrib><creatorcontrib>He, Siying</creatorcontrib><creatorcontrib>You, Qidong</creatorcontrib><creatorcontrib>Xiang, Hua</creatorcontrib><title>Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors</title><title>MedChemComm</title><addtitle>Medchemcomm</addtitle><description>BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary
in vitro
activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound
11g
displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC
50
= 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that
11g
inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that
11g
could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that
11g
was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases.</description><subject>Autoimmune diseases</subject><subject>Bruton's tyrosine kinase</subject><subject>Cell proliferation</subject><subject>Derivatives</subject><subject>Downstream effects</subject><subject>Flow cytometry</subject><subject>G1 phase</subject><subject>Lead compounds</subject><subject>Leukemia</subject><subject>Lymphatic leukemia</subject><subject>Lymphocytes B</subject><subject>Medical treatment</subject><subject>Optimization</subject><subject>Phospholipase</subject><subject>Phosphorylation</subject><subject>Protein-tyrosine kinase</subject><subject>Substrates</subject><subject>Time dependence</subject><subject>Tumors</subject><subject>Tyrosine</subject><issn>2040-2503</issn><issn>2040-2511</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNpd0U1PHCEYB3BibNRYL71rSHpwbToWhtlZONb1pU01veh5wsszu-gsjMBsMt-gH1vs2m0iFx7CL094-CP0iZJzSpj4pvnKEFJRtthBByWpSFFOKd3d1oTto6MYH0lerORcVHtonxHOaU3rA_TnEqJduK84ji4tcx2xdAYr6zu_sFp2GNayG2Sy3mHfYufX0OGy6Jfgxg73Y7Ara6wDbCDYdXZryC0i7n0Cl_BFGJJ3pxGnMfj46p6skxHw5OL-1xm2bmmVTT7Ej-hDK7sIR2_7IXq4vrqf_yhuf9_8nH-_LTSbsVRwYyTUpWatokJw4HlYIozh0NZcmGmrpkILMSVqBnVlSJmPSmmjFdS6ghk7RJNN3z745wFialY2aug66cAPsSmpYDUtuaCZfn5HH_0QXH5dVrxiomJEZPVlo3QeMAZomz7_iQxjQ0nzGlEz53eXfyO6yfjkreWgVmC29F8gGRxvQIh6e_s_Y_YCRHaXcA</recordid><startdate>20190201</startdate><enddate>20190201</enddate><creator>Li, Xinyu</creator><creator>Shi, Binyu</creator><creator>Teng, Yu</creator><creator>Cheng, Yu</creator><creator>Yang, Huizhu</creator><creator>Li, Jiurong</creator><creator>Wang, Lianjian</creator><creator>He, Siying</creator><creator>You, Qidong</creator><creator>Xiang, Hua</creator><general>Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T5</scope><scope>7T7</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8937-4062</orcidid></search><sort><creationdate>20190201</creationdate><title>Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors</title><author>Li, Xinyu ; Shi, Binyu ; Teng, Yu ; Cheng, Yu ; Yang, Huizhu ; Li, Jiurong ; Wang, Lianjian ; He, Siying ; You, Qidong ; Xiang, Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c373t-8ddae62c3fb1998e851109dd8ef689d5fb59c9950b7e64d0259cbbcdcbe6c4e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Autoimmune diseases</topic><topic>Bruton's tyrosine kinase</topic><topic>Cell proliferation</topic><topic>Derivatives</topic><topic>Downstream effects</topic><topic>Flow cytometry</topic><topic>G1 phase</topic><topic>Lead compounds</topic><topic>Leukemia</topic><topic>Lymphatic leukemia</topic><topic>Lymphocytes B</topic><topic>Medical treatment</topic><topic>Optimization</topic><topic>Phospholipase</topic><topic>Phosphorylation</topic><topic>Protein-tyrosine kinase</topic><topic>Substrates</topic><topic>Time dependence</topic><topic>Tumors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Xinyu</creatorcontrib><creatorcontrib>Shi, Binyu</creatorcontrib><creatorcontrib>Teng, Yu</creatorcontrib><creatorcontrib>Cheng, Yu</creatorcontrib><creatorcontrib>Yang, Huizhu</creatorcontrib><creatorcontrib>Li, Jiurong</creatorcontrib><creatorcontrib>Wang, Lianjian</creatorcontrib><creatorcontrib>He, Siying</creatorcontrib><creatorcontrib>You, Qidong</creatorcontrib><creatorcontrib>Xiang, Hua</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>MedChemComm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Xinyu</au><au>Shi, Binyu</au><au>Teng, Yu</au><au>Cheng, Yu</au><au>Yang, Huizhu</au><au>Li, Jiurong</au><au>Wang, Lianjian</au><au>He, Siying</au><au>You, Qidong</au><au>Xiang, Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors</atitle><jtitle>MedChemComm</jtitle><addtitle>Medchemcomm</addtitle><date>2019-02-01</date><risdate>2019</risdate><volume>1</volume><issue>2</issue><spage>294</spage><epage>299</epage><pages>294-299</pages><issn>2040-2503</issn><eissn>2040-2511</eissn><abstract>BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary
in vitro
activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound
11g
displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC
50
= 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that
11g
inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that
11g
could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that
11g
was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>30881616</pmid><doi>10.1039/c8md00413g</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-8937-4062</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Royal Society Of Chemistry Journals 2008-; PubMed Central |
| subjects | Autoimmune diseases Bruton's tyrosine kinase Cell proliferation Derivatives Downstream effects Flow cytometry G1 phase Lead compounds Leukemia Lymphatic leukemia Lymphocytes B Medical treatment Optimization Phospholipase Phosphorylation Protein-tyrosine kinase Substrates Time dependence Tumors Tyrosine |
| title | Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors |
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