Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors
A class of 4-phenoxy-pyridine/pyrimidine derivatives ( 23a-23p and 24a-24h ) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The in vitro anti-cancer cell proliferative activity of the compounds indicated that compound 23k was regarded as a promising derivative. Com...
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| Veröffentlicht in: | New journal of chemistry 2022-07, Vol.46 (26), p.12651-12665 |
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| creator | Yang, Feiyi Zhang, Qian Guo, Qiuyan Pan, Qingshan Wen, Chunping Lv, Xinya Zhu, Wufu Zheng, Pengwu |
| description | A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The
in vitro
anti-cancer cell proliferative activity of the compounds indicated that compound
23k
was regarded as a promising derivative. Compared to the lead compounds Foretinib and Sorafenib,
23k
showed excellent inhibitory activity against the A549, MCF-7, HepG2 and Ovcar-3 cell lines with IC
50
values of 2.16 ± 0.19 μM, 9.13 ± 0.65 μM, 20.15 ± 2.64 and 9.65 ± 0.51 μM, respectively. In addition,
23k
exhibited low toxicity to human normal cells (LO2 cells) with IC
50
values above 100 μM. In kinase assays, the most promising compound
23k
showed excellent kinase inhibitory activity and selectivity against VEGFR-2 and c-Met with IC
50
values of 1.05 and 1.43 μM, respectively. Further activity studies demonstrated that
23k
not only induced apoptosis in A549, but also blocked the A549 cell lines in the G0/G1 phase in a dose-dependent manner. Moreover, molecular docking and molecular dynamics simulation studies revealed the binding modes of
23k
to VEGFR-2 and c-Met. The binding modes and structure-activity relationship (SAR) investigations of synthetic pyridine/pyrimidine derivatives, as well as a brief mechanism of their anti-VEGFR-2 and c-Met kinase activities, are presented in this paper.
A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. |
| doi_str_mv | 10.1039/d2nj01561g |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1039_D2NJ01561G</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2684712187</sourcerecordid><originalsourceid>FETCH-LOGICAL-c281t-110de580321c807dbc02448b843e982b3e8d4eb74ab7b828a4aa8b9145df66ab3</originalsourceid><addsrcrecordid>eNpFkE1LAzEQhhdRsFYv3oWANzE2k83uZo_SL5WqIOp1STZpm1KTmuwW99-bWtHTPIdn3mHeJDkHcgMkLQeK2hWBLIfFQdKDNC9xSXM4jAyMYZKx_Dg5CWFFCECRQy_pRjqYhb1GobPNMnJAwiokjVu7hanFGumtWLeiMc4iN0cMb5bauq8ObzpvlLF6sIOPH0RKe7ON7lbHmIBUG_ffx9PJC6aDGj_qBhm7NNI0zofT5Ggu1kGf_c5-8jYZvw7v8Ox5ej-8neGacmgwAFE64ySlUHNSKFkTyhiXnKW65FSmmiumZcGELCSnXDAhuCyBZWqe50Km_eRyn7vx7rPVoalWrvU2nqxozlkBFHgRrau9VXsXgtfzahO_Er6rgFS7aqsRfXr4qXYa5Yu97EP95_1Xn34DTHN2lg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2684712187</pqid></control><display><type>article</type><title>Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors</title><source>Royal Society Of Chemistry Journals 2008-</source><source>Alma/SFX Local Collection</source><creator>Yang, Feiyi ; Zhang, Qian ; Guo, Qiuyan ; Pan, Qingshan ; Wen, Chunping ; Lv, Xinya ; Zhu, Wufu ; Zheng, Pengwu</creator><creatorcontrib>Yang, Feiyi ; Zhang, Qian ; Guo, Qiuyan ; Pan, Qingshan ; Wen, Chunping ; Lv, Xinya ; Zhu, Wufu ; Zheng, Pengwu</creatorcontrib><description>A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The
in vitro
anti-cancer cell proliferative activity of the compounds indicated that compound
23k
was regarded as a promising derivative. Compared to the lead compounds Foretinib and Sorafenib,
23k
showed excellent inhibitory activity against the A549, MCF-7, HepG2 and Ovcar-3 cell lines with IC
50
values of 2.16 ± 0.19 μM, 9.13 ± 0.65 μM, 20.15 ± 2.64 and 9.65 ± 0.51 μM, respectively. In addition,
23k
exhibited low toxicity to human normal cells (LO2 cells) with IC
50
values above 100 μM. In kinase assays, the most promising compound
23k
showed excellent kinase inhibitory activity and selectivity against VEGFR-2 and c-Met with IC
50
values of 1.05 and 1.43 μM, respectively. Further activity studies demonstrated that
23k
not only induced apoptosis in A549, but also blocked the A549 cell lines in the G0/G1 phase in a dose-dependent manner. Moreover, molecular docking and molecular dynamics simulation studies revealed the binding modes of
23k
to VEGFR-2 and c-Met. The binding modes and structure-activity relationship (SAR) investigations of synthetic pyridine/pyrimidine derivatives, as well as a brief mechanism of their anti-VEGFR-2 and c-Met kinase activities, are presented in this paper.
A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors.</description><identifier>ISSN: 1144-0546</identifier><identifier>EISSN: 1369-9261</identifier><identifier>DOI: 10.1039/d2nj01561g</identifier><language>eng</language><publisher>Cambridge: Royal Society of Chemistry</publisher><subject>Anticancer properties ; Apoptosis ; Binding ; Kinases ; Lead compounds ; Molecular docking ; Molecular dynamics ; Pyridines ; Selectivity ; Toxicity</subject><ispartof>New journal of chemistry, 2022-07, Vol.46 (26), p.12651-12665</ispartof><rights>Copyright Royal Society of Chemistry 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c281t-110de580321c807dbc02448b843e982b3e8d4eb74ab7b828a4aa8b9145df66ab3</citedby><cites>FETCH-LOGICAL-c281t-110de580321c807dbc02448b843e982b3e8d4eb74ab7b828a4aa8b9145df66ab3</cites><orcidid>0000-0001-6075-0450</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Yang, Feiyi</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Guo, Qiuyan</creatorcontrib><creatorcontrib>Pan, Qingshan</creatorcontrib><creatorcontrib>Wen, Chunping</creatorcontrib><creatorcontrib>Lv, Xinya</creatorcontrib><creatorcontrib>Zhu, Wufu</creatorcontrib><creatorcontrib>Zheng, Pengwu</creatorcontrib><title>Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors</title><title>New journal of chemistry</title><description>A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The
in vitro
anti-cancer cell proliferative activity of the compounds indicated that compound
23k
was regarded as a promising derivative. Compared to the lead compounds Foretinib and Sorafenib,
23k
showed excellent inhibitory activity against the A549, MCF-7, HepG2 and Ovcar-3 cell lines with IC
50
values of 2.16 ± 0.19 μM, 9.13 ± 0.65 μM, 20.15 ± 2.64 and 9.65 ± 0.51 μM, respectively. In addition,
23k
exhibited low toxicity to human normal cells (LO2 cells) with IC
50
values above 100 μM. In kinase assays, the most promising compound
23k
showed excellent kinase inhibitory activity and selectivity against VEGFR-2 and c-Met with IC
50
values of 1.05 and 1.43 μM, respectively. Further activity studies demonstrated that
23k
not only induced apoptosis in A549, but also blocked the A549 cell lines in the G0/G1 phase in a dose-dependent manner. Moreover, molecular docking and molecular dynamics simulation studies revealed the binding modes of
23k
to VEGFR-2 and c-Met. The binding modes and structure-activity relationship (SAR) investigations of synthetic pyridine/pyrimidine derivatives, as well as a brief mechanism of their anti-VEGFR-2 and c-Met kinase activities, are presented in this paper.
A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors.</description><subject>Anticancer properties</subject><subject>Apoptosis</subject><subject>Binding</subject><subject>Kinases</subject><subject>Lead compounds</subject><subject>Molecular docking</subject><subject>Molecular dynamics</subject><subject>Pyridines</subject><subject>Selectivity</subject><subject>Toxicity</subject><issn>1144-0546</issn><issn>1369-9261</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNpFkE1LAzEQhhdRsFYv3oWANzE2k83uZo_SL5WqIOp1STZpm1KTmuwW99-bWtHTPIdn3mHeJDkHcgMkLQeK2hWBLIfFQdKDNC9xSXM4jAyMYZKx_Dg5CWFFCECRQy_pRjqYhb1GobPNMnJAwiokjVu7hanFGumtWLeiMc4iN0cMb5bauq8ObzpvlLF6sIOPH0RKe7ON7lbHmIBUG_ffx9PJC6aDGj_qBhm7NNI0zofT5Ggu1kGf_c5-8jYZvw7v8Ox5ej-8neGacmgwAFE64ySlUHNSKFkTyhiXnKW65FSmmiumZcGELCSnXDAhuCyBZWqe50Km_eRyn7vx7rPVoalWrvU2nqxozlkBFHgRrau9VXsXgtfzahO_Er6rgFS7aqsRfXr4qXYa5Yu97EP95_1Xn34DTHN2lg</recordid><startdate>20220705</startdate><enddate>20220705</enddate><creator>Yang, Feiyi</creator><creator>Zhang, Qian</creator><creator>Guo, Qiuyan</creator><creator>Pan, Qingshan</creator><creator>Wen, Chunping</creator><creator>Lv, Xinya</creator><creator>Zhu, Wufu</creator><creator>Zheng, Pengwu</creator><general>Royal Society of Chemistry</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>H9R</scope><scope>JG9</scope><scope>KA0</scope><orcidid>https://orcid.org/0000-0001-6075-0450</orcidid></search><sort><creationdate>20220705</creationdate><title>Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors</title><author>Yang, Feiyi ; Zhang, Qian ; Guo, Qiuyan ; Pan, Qingshan ; Wen, Chunping ; Lv, Xinya ; Zhu, Wufu ; Zheng, Pengwu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c281t-110de580321c807dbc02448b843e982b3e8d4eb74ab7b828a4aa8b9145df66ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Anticancer properties</topic><topic>Apoptosis</topic><topic>Binding</topic><topic>Kinases</topic><topic>Lead compounds</topic><topic>Molecular docking</topic><topic>Molecular dynamics</topic><topic>Pyridines</topic><topic>Selectivity</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Feiyi</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Guo, Qiuyan</creatorcontrib><creatorcontrib>Pan, Qingshan</creatorcontrib><creatorcontrib>Wen, Chunping</creatorcontrib><creatorcontrib>Lv, Xinya</creatorcontrib><creatorcontrib>Zhu, Wufu</creatorcontrib><creatorcontrib>Zheng, Pengwu</creatorcontrib><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Illustrata: Natural Sciences</collection><collection>Materials Research Database</collection><collection>ProQuest Illustrata: Technology Collection</collection><jtitle>New journal of chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Feiyi</au><au>Zhang, Qian</au><au>Guo, Qiuyan</au><au>Pan, Qingshan</au><au>Wen, Chunping</au><au>Lv, Xinya</au><au>Zhu, Wufu</au><au>Zheng, Pengwu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors</atitle><jtitle>New journal of chemistry</jtitle><date>2022-07-05</date><risdate>2022</risdate><volume>46</volume><issue>26</issue><spage>12651</spage><epage>12665</epage><pages>12651-12665</pages><issn>1144-0546</issn><eissn>1369-9261</eissn><abstract>A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The
in vitro
anti-cancer cell proliferative activity of the compounds indicated that compound
23k
was regarded as a promising derivative. Compared to the lead compounds Foretinib and Sorafenib,
23k
showed excellent inhibitory activity against the A549, MCF-7, HepG2 and Ovcar-3 cell lines with IC
50
values of 2.16 ± 0.19 μM, 9.13 ± 0.65 μM, 20.15 ± 2.64 and 9.65 ± 0.51 μM, respectively. In addition,
23k
exhibited low toxicity to human normal cells (LO2 cells) with IC
50
values above 100 μM. In kinase assays, the most promising compound
23k
showed excellent kinase inhibitory activity and selectivity against VEGFR-2 and c-Met with IC
50
values of 1.05 and 1.43 μM, respectively. Further activity studies demonstrated that
23k
not only induced apoptosis in A549, but also blocked the A549 cell lines in the G0/G1 phase in a dose-dependent manner. Moreover, molecular docking and molecular dynamics simulation studies revealed the binding modes of
23k
to VEGFR-2 and c-Met. The binding modes and structure-activity relationship (SAR) investigations of synthetic pyridine/pyrimidine derivatives, as well as a brief mechanism of their anti-VEGFR-2 and c-Met kinase activities, are presented in this paper.
A class of 4-phenoxy-pyridine/pyrimidine derivatives (
23a-23p
and
24a-24h
) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors.</abstract><cop>Cambridge</cop><pub>Royal Society of Chemistry</pub><doi>10.1039/d2nj01561g</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-6075-0450</orcidid></addata></record> |
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| language | eng |
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| source | Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| subjects | Anticancer properties Apoptosis Binding Kinases Lead compounds Molecular docking Molecular dynamics Pyridines Selectivity Toxicity |
| title | Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors |
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