Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors
Small-molecule inhibitors that block the MDM2-p53 protein–protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We...
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| Veröffentlicht in: | Journal of the American Chemical Society 2013-05, Vol.135 (19), p.7223-7234 |
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| creator | Zhao, Yujun Liu, Liu Sun, Wei Lu, Jianfeng McEachern, Donna Li, Xiaoqin Yu, Shanghai Bernard, Denzil Ochsenbein, Philippe Ferey, Vincent Carry, Jean-Christophe Deschamps, Jeffrey R Sun, Duxin Wang, Shaomeng |
| description | Small-molecule inhibitors that block the MDM2-p53 protein–protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a K i value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer. |
| doi_str_mv | 10.1021/ja3125417 |
| format | Article |
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We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a K i value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.</description><identifier>ISSN: 0002-7863</identifier><identifier>ISSN: 1520-5126</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/ja3125417</identifier><identifier>PMID: 23641733</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>animal models ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; binding capacity ; Bone and Bones - drug effects ; Bone and Bones - metabolism ; Bone and Bones - pathology ; Bone Neoplasms - drug therapy ; Bone Neoplasms - metabolism ; Bone Neoplasms - pathology ; Cell Line, Tumor ; Cyclization ; diastereomers ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacokinetics ; Indoles - therapeutic use ; Mice, SCID ; Models, Molecular ; neoplasms ; Osteosarcoma - drug therapy ; Osteosarcoma - metabolism ; Osteosarcoma - pathology ; protein-protein interactions ; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2 - metabolism ; remission ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - therapeutic use ; stereochemistry ; Stereoisomerism</subject><ispartof>Journal of the American Chemical Society, 2013-05, Vol.135 (19), p.7223-7234</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a438t-b26642445e1fb4c5d25280371ab26d4ba649dd6d6753c83f4640ff2d4d7de42b3</citedby><cites>FETCH-LOGICAL-a438t-b26642445e1fb4c5d25280371ab26d4ba649dd6d6753c83f4640ff2d4d7de42b3</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/ja3125417$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/ja3125417$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23641733$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Yujun</creatorcontrib><creatorcontrib>Liu, Liu</creatorcontrib><creatorcontrib>Sun, Wei</creatorcontrib><creatorcontrib>Lu, Jianfeng</creatorcontrib><creatorcontrib>McEachern, Donna</creatorcontrib><creatorcontrib>Li, Xiaoqin</creatorcontrib><creatorcontrib>Yu, Shanghai</creatorcontrib><creatorcontrib>Bernard, Denzil</creatorcontrib><creatorcontrib>Ochsenbein, Philippe</creatorcontrib><creatorcontrib>Ferey, Vincent</creatorcontrib><creatorcontrib>Carry, Jean-Christophe</creatorcontrib><creatorcontrib>Deschamps, Jeffrey R</creatorcontrib><creatorcontrib>Sun, Duxin</creatorcontrib><creatorcontrib>Wang, Shaomeng</creatorcontrib><title>Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>Small-molecule inhibitors that block the MDM2-p53 protein–protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a K i value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.</description><subject>animal models</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>binding capacity</subject><subject>Bone and Bones - drug effects</subject><subject>Bone and Bones - metabolism</subject><subject>Bone and Bones - pathology</subject><subject>Bone Neoplasms - drug therapy</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cyclization</subject><subject>diastereomers</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacokinetics</subject><subject>Indoles - therapeutic use</subject><subject>Mice, SCID</subject><subject>Models, Molecular</subject><subject>neoplasms</subject><subject>Osteosarcoma - drug therapy</subject><subject>Osteosarcoma - metabolism</subject><subject>Osteosarcoma - pathology</subject><subject>protein-protein interactions</subject><subject>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>remission</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - therapeutic use</subject><subject>stereochemistry</subject><subject>Stereoisomerism</subject><issn>0002-7863</issn><issn>1520-5126</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1KAzEURoMotlYXvoDMRtDFaP5nuhGkrVZoVVDXIZNk2pTppCYzYt_eSGtRcHUJ9_DdLweAUwSvEMToeiEJwoyibA90EcMwZQjzfdCFEOI0yznpgKMQFvFJcY4OQQcTHmlCuuBxaGVojDduabxVycvKeuc-ba1dZUIiQzK2s3m1Tp5dY-omkbVORmVplVTWtSGZDqc4eajntrCN8-EYHJSyCuZkO3vg7W70Ohink6f7h8HtJJWU5E1aYM4pppQZVBZUMY0ZziHJkIwbTQvJaV9rrnnGiMpJSTmFZYk11Zk2FBekB242uau2WBqtYjUvK7Hydin9Wjhpxd9Nbedi5j4EySGHDMWAi22Ad--tCY1Y2qBMVcnaxH8JHGXFPpD1I3q5QZV3IXhT7s4gKL79i53_yJ797rUjf4RH4HwDSBXEwrW-jpr-CfoCokGMHw</recordid><startdate>20130515</startdate><enddate>20130515</enddate><creator>Zhao, Yujun</creator><creator>Liu, Liu</creator><creator>Sun, Wei</creator><creator>Lu, Jianfeng</creator><creator>McEachern, Donna</creator><creator>Li, Xiaoqin</creator><creator>Yu, Shanghai</creator><creator>Bernard, Denzil</creator><creator>Ochsenbein, Philippe</creator><creator>Ferey, Vincent</creator><creator>Carry, Jean-Christophe</creator><creator>Deschamps, Jeffrey R</creator><creator>Sun, Duxin</creator><creator>Wang, Shaomeng</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>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20130515</creationdate><title>Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors</title><author>Zhao, Yujun ; Liu, Liu ; Sun, Wei ; Lu, Jianfeng ; McEachern, Donna ; Li, Xiaoqin ; Yu, Shanghai ; Bernard, Denzil ; Ochsenbein, Philippe ; Ferey, Vincent ; Carry, Jean-Christophe ; Deschamps, Jeffrey R ; Sun, Duxin ; Wang, Shaomeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a438t-b26642445e1fb4c5d25280371ab26d4ba649dd6d6753c83f4640ff2d4d7de42b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>animal models</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>binding capacity</topic><topic>Bone and Bones - drug effects</topic><topic>Bone and Bones - metabolism</topic><topic>Bone and Bones - pathology</topic><topic>Bone Neoplasms - drug therapy</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cyclization</topic><topic>diastereomers</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacokinetics</topic><topic>Indoles - therapeutic use</topic><topic>Mice, SCID</topic><topic>Models, Molecular</topic><topic>neoplasms</topic><topic>Osteosarcoma - drug therapy</topic><topic>Osteosarcoma - metabolism</topic><topic>Osteosarcoma - pathology</topic><topic>protein-protein interactions</topic><topic>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>remission</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - therapeutic use</topic><topic>stereochemistry</topic><topic>Stereoisomerism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Yujun</creatorcontrib><creatorcontrib>Liu, Liu</creatorcontrib><creatorcontrib>Sun, Wei</creatorcontrib><creatorcontrib>Lu, Jianfeng</creatorcontrib><creatorcontrib>McEachern, Donna</creatorcontrib><creatorcontrib>Li, Xiaoqin</creatorcontrib><creatorcontrib>Yu, Shanghai</creatorcontrib><creatorcontrib>Bernard, Denzil</creatorcontrib><creatorcontrib>Ochsenbein, Philippe</creatorcontrib><creatorcontrib>Ferey, Vincent</creatorcontrib><creatorcontrib>Carry, Jean-Christophe</creatorcontrib><creatorcontrib>Deschamps, Jeffrey R</creatorcontrib><creatorcontrib>Sun, Duxin</creatorcontrib><creatorcontrib>Wang, Shaomeng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Chemical Society</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Yujun</au><au>Liu, Liu</au><au>Sun, Wei</au><au>Lu, Jianfeng</au><au>McEachern, Donna</au><au>Li, Xiaoqin</au><au>Yu, Shanghai</au><au>Bernard, Denzil</au><au>Ochsenbein, Philippe</au><au>Ferey, Vincent</au><au>Carry, Jean-Christophe</au><au>Deschamps, Jeffrey R</au><au>Sun, Duxin</au><au>Wang, Shaomeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors</atitle><jtitle>Journal of the American Chemical Society</jtitle><addtitle>J. Am. Chem. Soc</addtitle><date>2013-05-15</date><risdate>2013</risdate><volume>135</volume><issue>19</issue><spage>7223</spage><epage>7234</epage><pages>7223-7234</pages><issn>0002-7863</issn><issn>1520-5126</issn><eissn>1520-5126</eissn><abstract>Small-molecule inhibitors that block the MDM2-p53 protein–protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a K i value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23641733</pmid><doi>10.1021/ja3125417</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | animal models Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use binding capacity Bone and Bones - drug effects Bone and Bones - metabolism Bone and Bones - pathology Bone Neoplasms - drug therapy Bone Neoplasms - metabolism Bone Neoplasms - pathology Cell Line, Tumor Cyclization diastereomers Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacokinetics Indoles - therapeutic use Mice, SCID Models, Molecular neoplasms Osteosarcoma - drug therapy Osteosarcoma - metabolism Osteosarcoma - pathology protein-protein interactions Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors Proto-Oncogene Proteins c-mdm2 - metabolism remission Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacokinetics Spiro Compounds - therapeutic use stereochemistry Stereoisomerism |
| title | Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors |
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