Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex
Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53−/− SW480; the lung cancer cell line p53−/− H1299; mouse embry...
Gespeichert in:
| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2016/01/01, Vol.64(1), pp.34-41 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 41 |
|---|---|
| container_issue | 1 |
| container_start_page | 34 |
| container_title | Chemical & pharmaceutical bulletin |
| container_volume | 64 |
| creator | Rezk, Mohamed Salah Abdel-Halim, Mohammad Keeton, Adam Franklin, Derek Bauer, Matthias Boeckler, Frank Michael Engel, Matthias Hartmann, Rolf Wolfgang Zhang, Yanping Piazza, Gary Anthony Abadi, Ashraf Hassan |
| description | Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53−/− SW480; the lung cancer cell line p53−/− H1299; mouse embryonic fibroblasts (MEF) p53+/+ and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53+/+ cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3. |
| doi_str_mv | 10.1248/cpb.c15-00608 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1837322657</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1754093760</sourcerecordid><originalsourceid>FETCH-LOGICAL-c504t-6d18556e82d665e82457d3af395c9734203f34c353cc07e69ec70ab5bbe81a5c3</originalsourceid><addsrcrecordid>eNqFkU1v1DAQhiMEokvhyBVZ4sKBtI4_k-Nqt3xILT2wnC3Hmex6lTjBdpaWP8FfxtuUReKCZM0c_Mw7sp8se13gi4Kw8tKM9YUpeI6xwOWTbFFQJnNOCH2aLTDGVU6ooGfZixD2GBOOJX2enREh02Fkkf36eu_iDoINSLsG3Y7R9vanjnZwaGjRF_iB6HuRr22Y6hBtnCI01jVDB2gN3h4SeYB5drMD69HVQXfTPK8DWrpojXYGPFpuwcWANtpvIVq3RWktulnfkMtU7tBq6McO7l5mz1rdBXj12M-zbx-uNqtP-fXtx8-r5XVuOGYxF01Rci6gJI0QPDXGZUN1SytuKkkZwbSlzFBOjcESRAVGYl3zuoay0NzQ8-zdnDv64fsEIareBgNdpx0MU1BFSSUlRHD5f1RyhisqBU7o23_Q_TB5lx5ypCjlFSuPVD5Txg8heGjV6G2v_b0qsDpKVUmqSlLVg9TEv3lMneoemhP9x2ICVjOwD1Fv4QRon36_g4c4wVRxLKfYv7c77RU4-htYRbTB</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1753359480</pqid></control><display><type>article</type><title>Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex</title><source>J-STAGE Free</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Rezk, Mohamed Salah ; Abdel-Halim, Mohammad ; Keeton, Adam ; Franklin, Derek ; Bauer, Matthias ; Boeckler, Frank Michael ; Engel, Matthias ; Hartmann, Rolf Wolfgang ; Zhang, Yanping ; Piazza, Gary Anthony ; Abadi, Ashraf Hassan</creator><creatorcontrib>Rezk, Mohamed Salah ; Abdel-Halim, Mohammad ; Keeton, Adam ; Franklin, Derek ; Bauer, Matthias ; Boeckler, Frank Michael ; Engel, Matthias ; Hartmann, Rolf Wolfgang ; Zhang, Yanping ; Piazza, Gary Anthony ; Abadi, Ashraf Hassan</creatorcontrib><description>Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53−/− SW480; the lung cancer cell line p53−/− H1299; mouse embryonic fibroblasts (MEF) p53+/+ and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53+/+ cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.c15-00608</identifier><identifier>PMID: 26726742</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Humans ; indole derivative ; Indoles - chemistry ; Indoles - pharmacology ; Mice ; Molecular Structure ; murine double minute 2 (MDM2) ; murine double minute 4 (MDM4) ; p53 ; Protein Binding - drug effects ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Structure-Activity Relationship ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2016/01/01, Vol.64(1), pp.34-41</ispartof><rights>2016 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-6d18556e82d665e82457d3af395c9734203f34c353cc07e69ec70ab5bbe81a5c3</citedby><cites>FETCH-LOGICAL-c504t-6d18556e82d665e82457d3af395c9734203f34c353cc07e69ec70ab5bbe81a5c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26726742$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rezk, Mohamed Salah</creatorcontrib><creatorcontrib>Abdel-Halim, Mohammad</creatorcontrib><creatorcontrib>Keeton, Adam</creatorcontrib><creatorcontrib>Franklin, Derek</creatorcontrib><creatorcontrib>Bauer, Matthias</creatorcontrib><creatorcontrib>Boeckler, Frank Michael</creatorcontrib><creatorcontrib>Engel, Matthias</creatorcontrib><creatorcontrib>Hartmann, Rolf Wolfgang</creatorcontrib><creatorcontrib>Zhang, Yanping</creatorcontrib><creatorcontrib>Piazza, Gary Anthony</creatorcontrib><creatorcontrib>Abadi, Ashraf Hassan</creatorcontrib><title>Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53−/− SW480; the lung cancer cell line p53−/− H1299; mouse embryonic fibroblasts (MEF) p53+/+ and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53+/+ cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>indole derivative</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>murine double minute 2 (MDM2)</subject><subject>murine double minute 4 (MDM4)</subject><subject>p53</subject><subject>Protein Binding - drug effects</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhiMEokvhyBVZ4sKBtI4_k-Nqt3xILT2wnC3Hmex6lTjBdpaWP8FfxtuUReKCZM0c_Mw7sp8se13gi4Kw8tKM9YUpeI6xwOWTbFFQJnNOCH2aLTDGVU6ooGfZixD2GBOOJX2enREh02Fkkf36eu_iDoINSLsG3Y7R9vanjnZwaGjRF_iB6HuRr22Y6hBtnCI01jVDB2gN3h4SeYB5drMD69HVQXfTPK8DWrpojXYGPFpuwcWANtpvIVq3RWktulnfkMtU7tBq6McO7l5mz1rdBXj12M-zbx-uNqtP-fXtx8-r5XVuOGYxF01Rci6gJI0QPDXGZUN1SytuKkkZwbSlzFBOjcESRAVGYl3zuoay0NzQ8-zdnDv64fsEIareBgNdpx0MU1BFSSUlRHD5f1RyhisqBU7o23_Q_TB5lx5ypCjlFSuPVD5Txg8heGjV6G2v_b0qsDpKVUmqSlLVg9TEv3lMneoemhP9x2ICVjOwD1Fv4QRon36_g4c4wVRxLKfYv7c77RU4-htYRbTB</recordid><startdate>20160101</startdate><enddate>20160101</enddate><creator>Rezk, Mohamed Salah</creator><creator>Abdel-Halim, Mohammad</creator><creator>Keeton, Adam</creator><creator>Franklin, Derek</creator><creator>Bauer, Matthias</creator><creator>Boeckler, Frank Michael</creator><creator>Engel, Matthias</creator><creator>Hartmann, Rolf Wolfgang</creator><creator>Zhang, Yanping</creator><creator>Piazza, Gary Anthony</creator><creator>Abadi, Ashraf Hassan</creator><general>The Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160101</creationdate><title>Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex</title><author>Rezk, Mohamed Salah ; Abdel-Halim, Mohammad ; Keeton, Adam ; Franklin, Derek ; Bauer, Matthias ; Boeckler, Frank Michael ; Engel, Matthias ; Hartmann, Rolf Wolfgang ; Zhang, Yanping ; Piazza, Gary Anthony ; Abadi, Ashraf Hassan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-6d18556e82d665e82457d3af395c9734203f34c353cc07e69ec70ab5bbe81a5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>indole derivative</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>murine double minute 2 (MDM2)</topic><topic>murine double minute 4 (MDM4)</topic><topic>p53</topic><topic>Protein Binding - drug effects</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rezk, Mohamed Salah</creatorcontrib><creatorcontrib>Abdel-Halim, Mohammad</creatorcontrib><creatorcontrib>Keeton, Adam</creatorcontrib><creatorcontrib>Franklin, Derek</creatorcontrib><creatorcontrib>Bauer, Matthias</creatorcontrib><creatorcontrib>Boeckler, Frank Michael</creatorcontrib><creatorcontrib>Engel, Matthias</creatorcontrib><creatorcontrib>Hartmann, Rolf Wolfgang</creatorcontrib><creatorcontrib>Zhang, Yanping</creatorcontrib><creatorcontrib>Piazza, Gary Anthony</creatorcontrib><creatorcontrib>Abadi, Ashraf Hassan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rezk, Mohamed Salah</au><au>Abdel-Halim, Mohammad</au><au>Keeton, Adam</au><au>Franklin, Derek</au><au>Bauer, Matthias</au><au>Boeckler, Frank Michael</au><au>Engel, Matthias</au><au>Hartmann, Rolf Wolfgang</au><au>Zhang, Yanping</au><au>Piazza, Gary Anthony</au><au>Abadi, Ashraf Hassan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2016-01-01</date><risdate>2016</risdate><volume>64</volume><issue>1</issue><spage>34</spage><epage>41</epage><pages>34-41</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53−/− SW480; the lung cancer cell line p53−/− H1299; mouse embryonic fibroblasts (MEF) p53+/+ and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53+/+ cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>26726742</pmid><doi>10.1248/cpb.c15-00608</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-2363 |
| ispartof | Chemical and Pharmaceutical Bulletin, 2016/01/01, Vol.64(1), pp.34-41 |
| issn | 0009-2363 1347-5223 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1837322657 |
| source | J-STAGE Free; MEDLINE; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Humans indole derivative Indoles - chemistry Indoles - pharmacology Mice Molecular Structure murine double minute 2 (MDM2) murine double minute 4 (MDM4) p53 Protein Binding - drug effects Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-mdm2 - metabolism Structure-Activity Relationship Ubiquitin-Protein Ligases - metabolism |
| title | Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T13%3A30%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis%20and%20Optimization%20of%20New%203,6-Disubstitutedindole%20Derivatives%20and%20Their%20Evaluation%20as%20Anticancer%20Agents%20Targeting%20the%20MDM2/MDMx%20Complex&rft.jtitle=Chemical%20&%20pharmaceutical%20bulletin&rft.au=Rezk,%20Mohamed%20Salah&rft.date=2016-01-01&rft.volume=64&rft.issue=1&rft.spage=34&rft.epage=41&rft.pages=34-41&rft.issn=0009-2363&rft.eissn=1347-5223&rft_id=info:doi/10.1248/cpb.c15-00608&rft_dat=%3Cproquest_cross%3E1754093760%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1753359480&rft_id=info:pmid/26726742&rfr_iscdi=true |