Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors
A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour...
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| Veröffentlicht in: | European journal of medicinal chemistry 2012-07, Vol.53, p.64-75 |
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| container_title | European journal of medicinal chemistry |
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| creator | Bargiotti, Alberto Musso, Loana Dallavalle, Sabrina Merlini, Lucio Gallo, Grazia Ciacci, Andrea Giannini, Giuseppe Cabri, Walter Penco, Sergio Vesci, Loredana Castorina, Massimo Milazzo, Ferdinando Maria Cervoni, Maria Luisa Barbarino, Marcella Pisano, Claudio Giommarelli, Chiara Zuco, Valentina De Cesare, Michelandrea Zunino, Franco |
| description | A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
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► A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized. ► The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression. ► Most of the compounds exhibited potent antiproliferative activity. ► The in vivo activity of a representative compound was evaluated. |
| doi_str_mv | 10.1016/j.ejmech.2012.03.036 |
| format | Article |
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[Display omitted]
► A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized. ► The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression. ► Most of the compounds exhibited potent antiproliferative activity. ► The in vivo activity of a representative compound was evaluated.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2012.03.036</identifier><identifier>PMID: 22538015</identifier><identifier>CODEN: EJMCA5</identifier><language>eng</language><publisher>Kidlington: Elsevier Masson SAS</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antiproliferative activity ; Antitumour ; Biological and medical sciences ; Cell Line, Tumor ; Female ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; HSP90 Heat-Shock Proteins - chemistry ; Hsp90 inhibitors ; Humans ; Inhibitory Concentration 50 ; Isoxazoles - chemistry ; Isoxazolonaphthoquinones ; Medical sciences ; Mice ; Miscellaneous ; Models, Molecular ; Naphthoquinones - chemical synthesis ; Naphthoquinones - chemistry ; Naphthoquinones - pharmacology ; Pharmacology. Drug treatments ; Protein Conformation ; QSAR ; Quantitative Structure-Activity Relationship ; Synthesis ; Xenograft Model Antitumor Assays</subject><ispartof>European journal of medicinal chemistry, 2012-07, Vol.53, p.64-75</ispartof><rights>2012 Elsevier Masson SAS</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c392t-3b8f151482dcf9eda9047491c696138d21eaa6c8558376bc77de6041f32112603</citedby><cites>FETCH-LOGICAL-c392t-3b8f151482dcf9eda9047491c696138d21eaa6c8558376bc77de6041f32112603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523412001985$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25974892$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22538015$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bargiotti, Alberto</creatorcontrib><creatorcontrib>Musso, Loana</creatorcontrib><creatorcontrib>Dallavalle, Sabrina</creatorcontrib><creatorcontrib>Merlini, Lucio</creatorcontrib><creatorcontrib>Gallo, Grazia</creatorcontrib><creatorcontrib>Ciacci, Andrea</creatorcontrib><creatorcontrib>Giannini, Giuseppe</creatorcontrib><creatorcontrib>Cabri, Walter</creatorcontrib><creatorcontrib>Penco, Sergio</creatorcontrib><creatorcontrib>Vesci, Loredana</creatorcontrib><creatorcontrib>Castorina, Massimo</creatorcontrib><creatorcontrib>Milazzo, Ferdinando Maria</creatorcontrib><creatorcontrib>Cervoni, Maria Luisa</creatorcontrib><creatorcontrib>Barbarino, Marcella</creatorcontrib><creatorcontrib>Pisano, Claudio</creatorcontrib><creatorcontrib>Giommarelli, Chiara</creatorcontrib><creatorcontrib>Zuco, Valentina</creatorcontrib><creatorcontrib>De Cesare, Michelandrea</creatorcontrib><creatorcontrib>Zunino, Franco</creatorcontrib><title>Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
[Display omitted]
► A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized. ► The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression. ► Most of the compounds exhibited potent antiproliferative activity. ► The in vivo activity of a representative compound was evaluated.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antiproliferative activity</subject><subject>Antitumour</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Female</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - chemistry</subject><subject>Hsp90 inhibitors</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazolonaphthoquinones</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Naphthoquinones - chemical synthesis</subject><subject>Naphthoquinones - chemistry</subject><subject>Naphthoquinones - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Conformation</subject><subject>QSAR</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Synthesis</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LI0EQhptlxUTXfyAylwU9TOyP6Y_ZgxBEjSB4cc9Np6eGdJhMZ7smu5pfb4dk9Sa8UJfnrSoeQs4ZnTDK1PVyAssV-MWEU8YnVOSob2TMtDKl4LL6TsaUc1FKLqoROUFcUkqlovSYjDiXwlAmx2T2iPHVbWMXL93WXfVuvRgW8c8m9LEH_FVMix7-Fb5ziEVsC_82xCG-Bl_McF3TIvSLMA9DTPiDHLWuQzg7zFPy-_7u5XZWPj0_PN5On0ovaj6UYm5aJllleOPbGhpX00pXNfOqVkyYhjNwTnkjpRFazb3WDShasVZwxrii4pRc7veuU34TcLCrgB66zvUQN2izG62VZtpktNqjPkXEBK1dp7By6S1DO07Zpd07tDuHlooclWsXhwub-Qqaj9J_aRn4eQAcete1yfU-4Ccna12ZmmfuZs9B9vE3QLLoA_QempDAD7aJ4etP3gGvrI-v</recordid><startdate>20120701</startdate><enddate>20120701</enddate><creator>Bargiotti, Alberto</creator><creator>Musso, Loana</creator><creator>Dallavalle, Sabrina</creator><creator>Merlini, Lucio</creator><creator>Gallo, Grazia</creator><creator>Ciacci, Andrea</creator><creator>Giannini, Giuseppe</creator><creator>Cabri, Walter</creator><creator>Penco, Sergio</creator><creator>Vesci, Loredana</creator><creator>Castorina, Massimo</creator><creator>Milazzo, Ferdinando Maria</creator><creator>Cervoni, Maria Luisa</creator><creator>Barbarino, Marcella</creator><creator>Pisano, Claudio</creator><creator>Giommarelli, Chiara</creator><creator>Zuco, Valentina</creator><creator>De Cesare, Michelandrea</creator><creator>Zunino, Franco</creator><general>Elsevier Masson SAS</general><general>Elsevier</general><scope>IQODW</scope><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>20120701</creationdate><title>Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors</title><author>Bargiotti, Alberto ; Musso, Loana ; Dallavalle, Sabrina ; Merlini, Lucio ; Gallo, Grazia ; Ciacci, Andrea ; Giannini, Giuseppe ; Cabri, Walter ; Penco, Sergio ; Vesci, Loredana ; Castorina, Massimo ; Milazzo, Ferdinando Maria ; Cervoni, Maria Luisa ; Barbarino, Marcella ; Pisano, Claudio ; Giommarelli, Chiara ; Zuco, Valentina ; De Cesare, Michelandrea ; Zunino, Franco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c392t-3b8f151482dcf9eda9047491c696138d21eaa6c8558376bc77de6041f32112603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antiproliferative activity</topic><topic>Antitumour</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Female</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - chemistry</topic><topic>Hsp90 inhibitors</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Isoxazoles - chemistry</topic><topic>Isoxazolonaphthoquinones</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Naphthoquinones - chemical synthesis</topic><topic>Naphthoquinones - chemistry</topic><topic>Naphthoquinones - pharmacology</topic><topic>Pharmacology. 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The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
[Display omitted]
► A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized. ► The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression. ► Most of the compounds exhibited potent antiproliferative activity. ► The in vivo activity of a representative compound was evaluated.</abstract><cop>Kidlington</cop><pub>Elsevier Masson SAS</pub><pmid>22538015</pmid><doi>10.1016/j.ejmech.2012.03.036</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | European journal of medicinal chemistry, 2012-07, Vol.53, p.64-75 |
| issn | 0223-5234 1768-3254 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antiproliferative activity Antitumour Biological and medical sciences Cell Line, Tumor Female HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - chemistry Hsp90 inhibitors Humans Inhibitory Concentration 50 Isoxazoles - chemistry Isoxazolonaphthoquinones Medical sciences Mice Miscellaneous Models, Molecular Naphthoquinones - chemical synthesis Naphthoquinones - chemistry Naphthoquinones - pharmacology Pharmacology. Drug treatments Protein Conformation QSAR Quantitative Structure-Activity Relationship Synthesis Xenograft Model Antitumor Assays |
| title | Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors |
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