Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile
A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 15...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-08, Vol.53 (16), p.5929-5941 |
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| container_title | Journal of medicinal chemistry |
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| creator | Chiang, Chao-Cheng Lin, Yu-Hsiang Lin, Shu Fu Lai, Chun-Liang Liu, Chiawei Wei, Win-Yin Yang, Sheng-chuan Wang, Ru-Wen Teng, Li-Wei Chuang, Shih-Hsien Chang, Jia-Ming Yuan, Ta-Tung Lee, Ying-Shuen Chen, Paonien Chi, Wei-Kuang Yang, Ju-Ying Huang, Hung-Jyun Liao, Chu-Bin Huang, Jiann-Jyh |
| description | A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots. |
| doi_str_mv | 10.1021/jm1001869 |
| format | Article |
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The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm1001869</identifier><identifier>PMID: 20681538</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Aurora Kinase B ; Aurora Kinases ; Cell Proliferation - drug effects ; Drug Screening Assays, Antitumor ; HCT116 Cells ; HeLa Cells ; Histones - metabolism ; HT29 Cells ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Models, Molecular ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2010-08, Vol.53 (16), p.5929-5941</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-d0a741cb71c6218cba5261ebc135b44f02f7f737c6f3ecfd118e779d47fd7cb3</citedby><cites>FETCH-LOGICAL-a314t-d0a741cb71c6218cba5261ebc135b44f02f7f737c6f3ecfd118e779d47fd7cb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm1001869$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm1001869$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20681538$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chiang, Chao-Cheng</creatorcontrib><creatorcontrib>Lin, Yu-Hsiang</creatorcontrib><creatorcontrib>Lin, Shu Fu</creatorcontrib><creatorcontrib>Lai, Chun-Liang</creatorcontrib><creatorcontrib>Liu, Chiawei</creatorcontrib><creatorcontrib>Wei, Win-Yin</creatorcontrib><creatorcontrib>Yang, Sheng-chuan</creatorcontrib><creatorcontrib>Wang, Ru-Wen</creatorcontrib><creatorcontrib>Teng, Li-Wei</creatorcontrib><creatorcontrib>Chuang, Shih-Hsien</creatorcontrib><creatorcontrib>Chang, Jia-Ming</creatorcontrib><creatorcontrib>Yuan, Ta-Tung</creatorcontrib><creatorcontrib>Lee, Ying-Shuen</creatorcontrib><creatorcontrib>Chen, Paonien</creatorcontrib><creatorcontrib>Chi, Wei-Kuang</creatorcontrib><creatorcontrib>Yang, Ju-Ying</creatorcontrib><creatorcontrib>Huang, Hung-Jyun</creatorcontrib><creatorcontrib>Liao, Chu-Bin</creatorcontrib><creatorcontrib>Huang, Jiann-Jyh</creatorcontrib><title>Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Aurora Kinase B</subject><subject>Aurora Kinases</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Screening Assays, Antitumor</subject><subject>HCT116 Cells</subject><subject>HeLa Cells</subject><subject>Histones - metabolism</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Models, Molecular</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkL1OwzAURi0EouVn4AWQF4QYAr52EqcjavmpQKJD98hxrlVXqV3sBNQ3YOYReRKCCp2Y7nCPjvQdQs6AXQPjcLNcAWNQ5KM9MoSMsyQtWLpPhoxxnvCciwE5inHJGBPAxSEZcJYXkIliSMzERu3fMGyoN3S2CcE3-PXxOXW1b6zDhCfeYaQq0tsu-KDok3UqIp26ha1s60Ok77ZdUEUn1hgM6Nq_n_WOzoI3tsETcmBUE_H09x6T-f3dfPyYPL88TMe3z4kSkLZJzZRMQVcSdM6h0JXKeA5YaRBZlaaGcSONFFLnRqA2NUCBUo7qVJpa6kock8utdh38a4exLVf9PGwa5dB3sZRpMcrzLBv15NWW1MHHGNCU62BXKmxKYOVP1HIXtWfPf61dtcJ6R_5V7IGLLaB0LJe-C67f-I_oG9rGfxM</recordid><startdate>20100826</startdate><enddate>20100826</enddate><creator>Chiang, Chao-Cheng</creator><creator>Lin, Yu-Hsiang</creator><creator>Lin, Shu Fu</creator><creator>Lai, Chun-Liang</creator><creator>Liu, Chiawei</creator><creator>Wei, Win-Yin</creator><creator>Yang, Sheng-chuan</creator><creator>Wang, Ru-Wen</creator><creator>Teng, Li-Wei</creator><creator>Chuang, Shih-Hsien</creator><creator>Chang, Jia-Ming</creator><creator>Yuan, Ta-Tung</creator><creator>Lee, Ying-Shuen</creator><creator>Chen, Paonien</creator><creator>Chi, Wei-Kuang</creator><creator>Yang, Ju-Ying</creator><creator>Huang, Hung-Jyun</creator><creator>Liao, Chu-Bin</creator><creator>Huang, Jiann-Jyh</creator><general>American Chemical Society</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></search><sort><creationdate>20100826</creationdate><title>Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile</title><author>Chiang, Chao-Cheng ; Lin, Yu-Hsiang ; Lin, Shu Fu ; Lai, Chun-Liang ; Liu, Chiawei ; Wei, Win-Yin ; Yang, Sheng-chuan ; Wang, Ru-Wen ; Teng, Li-Wei ; Chuang, Shih-Hsien ; Chang, Jia-Ming ; Yuan, Ta-Tung ; Lee, Ying-Shuen ; Chen, Paonien ; Chi, Wei-Kuang ; Yang, Ju-Ying ; Huang, Hung-Jyun ; Liao, Chu-Bin ; Huang, Jiann-Jyh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-d0a741cb71c6218cba5261ebc135b44f02f7f737c6f3ecfd118e779d47fd7cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Aurora Kinase B</topic><topic>Aurora Kinases</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Screening Assays, Antitumor</topic><topic>HCT116 Cells</topic><topic>HeLa Cells</topic><topic>Histones - metabolism</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Models, Molecular</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chiang, Chao-Cheng</creatorcontrib><creatorcontrib>Lin, Yu-Hsiang</creatorcontrib><creatorcontrib>Lin, Shu Fu</creatorcontrib><creatorcontrib>Lai, Chun-Liang</creatorcontrib><creatorcontrib>Liu, Chiawei</creatorcontrib><creatorcontrib>Wei, Win-Yin</creatorcontrib><creatorcontrib>Yang, Sheng-chuan</creatorcontrib><creatorcontrib>Wang, Ru-Wen</creatorcontrib><creatorcontrib>Teng, Li-Wei</creatorcontrib><creatorcontrib>Chuang, Shih-Hsien</creatorcontrib><creatorcontrib>Chang, Jia-Ming</creatorcontrib><creatorcontrib>Yuan, Ta-Tung</creatorcontrib><creatorcontrib>Lee, Ying-Shuen</creatorcontrib><creatorcontrib>Chen, Paonien</creatorcontrib><creatorcontrib>Chi, Wei-Kuang</creatorcontrib><creatorcontrib>Yang, Ju-Ying</creatorcontrib><creatorcontrib>Huang, Hung-Jyun</creatorcontrib><creatorcontrib>Liao, Chu-Bin</creatorcontrib><creatorcontrib>Huang, Jiann-Jyh</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chiang, Chao-Cheng</au><au>Lin, Yu-Hsiang</au><au>Lin, Shu Fu</au><au>Lai, Chun-Liang</au><au>Liu, Chiawei</au><au>Wei, Win-Yin</au><au>Yang, Sheng-chuan</au><au>Wang, Ru-Wen</au><au>Teng, Li-Wei</au><au>Chuang, Shih-Hsien</au><au>Chang, Jia-Ming</au><au>Yuan, Ta-Tung</au><au>Lee, Ying-Shuen</au><au>Chen, Paonien</au><au>Chi, Wei-Kuang</au><au>Yang, Ju-Ying</au><au>Huang, Hung-Jyun</au><au>Liao, Chu-Bin</au><au>Huang, Jiann-Jyh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-08-26</date><risdate>2010</risdate><volume>53</volume><issue>16</issue><spage>5929</spage><epage>5941</epage><pages>5929-5941</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20681538</pmid><doi>10.1021/jm1001869</doi><tpages>13</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Aurora Kinase B Aurora Kinases Cell Proliferation - drug effects Drug Screening Assays, Antitumor HCT116 Cells HeLa Cells Histones - metabolism HT29 Cells Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Models, Molecular Phosphorylation Protein Binding Protein-Serine-Threonine Kinases - antagonists & inhibitors Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Stereoisomerism Structure-Activity Relationship |
| title | Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile |
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