Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors
Pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold 4 with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds 10 , 20 , and 22–24 which demonstrated subnanomolar IC 50 values in the biochemical assay. The potent compound 20 i...
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| Veröffentlicht in: | RSC advances 2014-01, Vol.4 (103), p.58990-58998 |
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| creator | Liu, Chia-Wei Lai, Chun-Liang Lin, Yu-Hsiang Teng, Li-Wei Yang, Sheng-chuan Wei, Win-Yin Lin, Shu Fu Yang, Ju-Ying Huang, Hung-Jyun Wang, Ru-Wen Chiang, Chao-Cheng Lee, Mei-Hui Wang, Yu-Chuan Chuang, Shih-Hsien Chang, Jia-Ming Lee, Ying-Shuan E. Huang, Jiann-Jyh |
| description | Pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold
4
with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds
10
,
20
, and
22–24
which demonstrated subnanomolar IC
50
values in the biochemical assay. The potent compound
20
inhibited Met with IC
50
value of 0.37 nM and the proliferation of MKN45 cells with IC
50
of 0.22 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with
20
at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of
20
with Met. |
| doi_str_mv | 10.1039/C4RA08720H |
| format | Article |
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4
with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds
10
,
20
, and
22–24
which demonstrated subnanomolar IC
50
values in the biochemical assay. The potent compound
20
inhibited Met with IC
50
value of 0.37 nM and the proliferation of MKN45 cells with IC
50
of 0.22 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with
20
at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of
20
with Met.</description><identifier>ISSN: 2046-2069</identifier><identifier>EISSN: 2046-2069</identifier><identifier>DOI: 10.1039/C4RA08720H</identifier><language>eng</language><subject>Biochemistry ; Computation ; Computer simulation ; Inhibitors ; Kinases ; Optimization ; Scaffolds ; Synthesis</subject><ispartof>RSC advances, 2014-01, Vol.4 (103), p.58990-58998</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c264t-69ed8a8917d4f0552686fb372ef9170d4224ca3c245449559b1513891f019433</citedby><cites>FETCH-LOGICAL-c264t-69ed8a8917d4f0552686fb372ef9170d4224ca3c245449559b1513891f019433</cites></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>Liu, Chia-Wei</creatorcontrib><creatorcontrib>Lai, Chun-Liang</creatorcontrib><creatorcontrib>Lin, Yu-Hsiang</creatorcontrib><creatorcontrib>Teng, Li-Wei</creatorcontrib><creatorcontrib>Yang, Sheng-chuan</creatorcontrib><creatorcontrib>Wei, Win-Yin</creatorcontrib><creatorcontrib>Lin, Shu Fu</creatorcontrib><creatorcontrib>Yang, Ju-Ying</creatorcontrib><creatorcontrib>Huang, Hung-Jyun</creatorcontrib><creatorcontrib>Wang, Ru-Wen</creatorcontrib><creatorcontrib>Chiang, Chao-Cheng</creatorcontrib><creatorcontrib>Lee, Mei-Hui</creatorcontrib><creatorcontrib>Wang, Yu-Chuan</creatorcontrib><creatorcontrib>Chuang, Shih-Hsien</creatorcontrib><creatorcontrib>Chang, Jia-Ming</creatorcontrib><creatorcontrib>Lee, Ying-Shuan E.</creatorcontrib><creatorcontrib>Huang, Jiann-Jyh</creatorcontrib><title>Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors</title><title>RSC advances</title><description>Pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold
4
with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds
10
,
20
, and
22–24
which demonstrated subnanomolar IC
50
values in the biochemical assay. The potent compound
20
inhibited Met with IC
50
value of 0.37 nM and the proliferation of MKN45 cells with IC
50
of 0.22 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with
20
at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of
20
with Met.</description><subject>Biochemistry</subject><subject>Computation</subject><subject>Computer simulation</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Optimization</subject><subject>Scaffolds</subject><subject>Synthesis</subject><issn>2046-2069</issn><issn>2046-2069</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNpNkM1Kw0AUhYMoWLQbn2CWVRyd_yTLUn8qVATpPkySiRlNZ-LcFImrrnwB38RH6pMYqaB3ce45l4-7OFF0QskFJTy9nInHKUliRuZ70YgRoTAjKt3_5w-jMcAzGUZJyhQdRR9XBuyTQ9qVCHrX1UME5CvU9iH4xmw3nxJP2LnCpS3qxgefG_feN6ewbirv-sa60g-CGfbOAHqzXY1mmG83XwhsaVBRa-sAaUCt74zr0L3p0It1Ggyyrra57XyA4-ig0g2Y8e8-ipY318vZHC8ebu9m0wUumBIdVqkpE52kNC5FRaRkKlFVzmNmquFGSsGYKDQvmJBCpFKmOZWUD3xFaCo4P4omu7dt8K9rA122slCYptHO-DVkNOaECMl5PKBnO7QIHiCYKmuDXenQZ5RkP3Vnf3Xzb2mVc0w</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Liu, Chia-Wei</creator><creator>Lai, Chun-Liang</creator><creator>Lin, Yu-Hsiang</creator><creator>Teng, Li-Wei</creator><creator>Yang, Sheng-chuan</creator><creator>Wei, Win-Yin</creator><creator>Lin, Shu Fu</creator><creator>Yang, Ju-Ying</creator><creator>Huang, Hung-Jyun</creator><creator>Wang, Ru-Wen</creator><creator>Chiang, Chao-Cheng</creator><creator>Lee, Mei-Hui</creator><creator>Wang, Yu-Chuan</creator><creator>Chuang, Shih-Hsien</creator><creator>Chang, Jia-Ming</creator><creator>Lee, Ying-Shuan E.</creator><creator>Huang, Jiann-Jyh</creator><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope></search><sort><creationdate>20140101</creationdate><title>Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors</title><author>Liu, Chia-Wei ; Lai, Chun-Liang ; Lin, Yu-Hsiang ; Teng, Li-Wei ; Yang, Sheng-chuan ; Wei, Win-Yin ; Lin, Shu Fu ; Yang, Ju-Ying ; Huang, Hung-Jyun ; Wang, Ru-Wen ; Chiang, Chao-Cheng ; Lee, Mei-Hui ; Wang, Yu-Chuan ; Chuang, Shih-Hsien ; Chang, Jia-Ming ; Lee, Ying-Shuan E. ; Huang, Jiann-Jyh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c264t-69ed8a8917d4f0552686fb372ef9170d4224ca3c245449559b1513891f019433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Biochemistry</topic><topic>Computation</topic><topic>Computer simulation</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Optimization</topic><topic>Scaffolds</topic><topic>Synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Chia-Wei</creatorcontrib><creatorcontrib>Lai, Chun-Liang</creatorcontrib><creatorcontrib>Lin, Yu-Hsiang</creatorcontrib><creatorcontrib>Teng, Li-Wei</creatorcontrib><creatorcontrib>Yang, Sheng-chuan</creatorcontrib><creatorcontrib>Wei, Win-Yin</creatorcontrib><creatorcontrib>Lin, Shu Fu</creatorcontrib><creatorcontrib>Yang, Ju-Ying</creatorcontrib><creatorcontrib>Huang, Hung-Jyun</creatorcontrib><creatorcontrib>Wang, Ru-Wen</creatorcontrib><creatorcontrib>Chiang, Chao-Cheng</creatorcontrib><creatorcontrib>Lee, Mei-Hui</creatorcontrib><creatorcontrib>Wang, Yu-Chuan</creatorcontrib><creatorcontrib>Chuang, Shih-Hsien</creatorcontrib><creatorcontrib>Chang, Jia-Ming</creatorcontrib><creatorcontrib>Lee, Ying-Shuan E.</creatorcontrib><creatorcontrib>Huang, Jiann-Jyh</creatorcontrib><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><jtitle>RSC advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Chia-Wei</au><au>Lai, Chun-Liang</au><au>Lin, Yu-Hsiang</au><au>Teng, Li-Wei</au><au>Yang, Sheng-chuan</au><au>Wei, Win-Yin</au><au>Lin, Shu Fu</au><au>Yang, Ju-Ying</au><au>Huang, Hung-Jyun</au><au>Wang, Ru-Wen</au><au>Chiang, Chao-Cheng</au><au>Lee, Mei-Hui</au><au>Wang, Yu-Chuan</au><au>Chuang, Shih-Hsien</au><au>Chang, Jia-Ming</au><au>Lee, Ying-Shuan E.</au><au>Huang, Jiann-Jyh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors</atitle><jtitle>RSC advances</jtitle><date>2014-01-01</date><risdate>2014</risdate><volume>4</volume><issue>103</issue><spage>58990</spage><epage>58998</epage><pages>58990-58998</pages><issn>2046-2069</issn><eissn>2046-2069</eissn><abstract>Pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold
4
with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds
10
,
20
, and
22–24
which demonstrated subnanomolar IC
50
values in the biochemical assay. The potent compound
20
inhibited Met with IC
50
value of 0.37 nM and the proliferation of MKN45 cells with IC
50
of 0.22 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with
20
at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of
20
with Met.</abstract><doi>10.1039/C4RA08720H</doi><tpages>9</tpages></addata></record> |
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| source | Royal Society Of Chemistry Journals 2008- |
| subjects | Biochemistry Computation Computer simulation Inhibitors Kinases Optimization Scaffolds Synthesis |
| title | Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors |
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