Synthesis and Biological Evaluation of Purealin and Analogues as Cytoplasmic Dynein Heavy Chain Inhibitors
Cytoplasmic dynein plays important roles in membrane transport, mitosis, and other cellular processes. A few small-molecule inhibitors of cytoplasmic dynein have been identified. We report here the first synthesis of purealin, a natural product isolated from the sea sponge Psammaplysilla purea, whic...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-03, Vol.49 (6), p.2063-2076 |
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| container_issue | 6 |
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| container_title | Journal of medicinal chemistry |
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| creator | Zhu, Guangyu Yang, Fanglong Balachandran, Raghavan Höök, Peter Vallee, Richard B Curran, Dennis P Day, Billy W |
| description | Cytoplasmic dynein plays important roles in membrane transport, mitosis, and other cellular processes. A few small-molecule inhibitors of cytoplasmic dynein have been identified. We report here the first synthesis of purealin, a natural product isolated from the sea sponge Psammaplysilla purea, which is known to inhibit axonemal dynein. Also described are the first syntheses, by modular amide coupling reactions, of the natural product purealidin A (a component of purealin) and a small library of analogues. The library was examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line but selective activities against human carcinoma cell lines. Purealin and some of the analogues inhibited the microtubule-stimulated ATPase activity of recombinant cytoplasmic dynein heavy chain motor domain. The inhibitory effect of purealin was concentration dependent and uncompetitive, supporting the hypothesis that it does not compete with the binding of ATP. |
| doi_str_mv | 10.1021/jm051030l |
| format | Article |
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A few small-molecule inhibitors of cytoplasmic dynein have been identified. We report here the first synthesis of purealin, a natural product isolated from the sea sponge Psammaplysilla purea, which is known to inhibit axonemal dynein. Also described are the first syntheses, by modular amide coupling reactions, of the natural product purealidin A (a component of purealin) and a small library of analogues. The library was examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line but selective activities against human carcinoma cell lines. Purealin and some of the analogues inhibited the microtubule-stimulated ATPase activity of recombinant cytoplasmic dynein heavy chain motor domain. The inhibitory effect of purealin was concentration dependent and uncompetitive, supporting the hypothesis that it does not compete with the binding of ATP.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm051030l</identifier><identifier>PMID: 16539395</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Adenosine Triphosphatases - chemistry ; Animals ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Bromobenzenes - chemical synthesis ; Bromobenzenes - chemistry ; Bromobenzenes - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cytoplasm - enzymology ; Drug Screening Assays, Antitumor ; Dyneins - antagonists & inhibitors ; General aspects ; Humans ; Kinetics ; Medical sciences ; Mice ; Pharmacology. 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Med. Chem</addtitle><description>Cytoplasmic dynein plays important roles in membrane transport, mitosis, and other cellular processes. A few small-molecule inhibitors of cytoplasmic dynein have been identified. We report here the first synthesis of purealin, a natural product isolated from the sea sponge Psammaplysilla purea, which is known to inhibit axonemal dynein. Also described are the first syntheses, by modular amide coupling reactions, of the natural product purealidin A (a component of purealin) and a small library of analogues. The library was examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line but selective activities against human carcinoma cell lines. Purealin and some of the analogues inhibited the microtubule-stimulated ATPase activity of recombinant cytoplasmic dynein heavy chain motor domain. The inhibitory effect of purealin was concentration dependent and uncompetitive, supporting the hypothesis that it does not compete with the binding of ATP.</description><subject>Adenosine Triphosphatases - chemistry</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bromobenzenes - chemical synthesis</subject><subject>Bromobenzenes - chemistry</subject><subject>Bromobenzenes - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cytoplasm - enzymology</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Dyneins - antagonists & inhibitors</subject><subject>General aspects</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Porifera</subject><subject>Protein Structure, Tertiary</subject><subject>Rats</subject><subject>Recombinant Proteins - chemistry</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0Mtu1DAUBmALUbVD2wUvgLIBiUXAl9jJLMvQmzSoRS1r68TjMB4ce_BJKvL2uMyo7YKVLfnz0X9-Qt4y-olRzj5veioZFdS_IjMmOS2rhlavyYxSzkuuuDgibxA3lFLBuDgkR0xJMRdzOSObuykMa4sOCwir4ouLPv50Bnxx_gB-hMHFUMSuuB2TBe_CP3UWIKvR5j9YLKYhbj1g70zxdQo2mysLD1OxWEO-X4e1a90QE56Qgw482tP9eUx-XJzfL67K5c3l9eJsWYJo2FCCbI1qGyWrOW2Fhaqyc8WZbYwBLisujBE1CNZxUVWccW55Z1ZyRZUxeSchjsmH3dxtir9zyEH3Do31HoKNI2pV11Jx3mT4cQdNiojJdnqbXA9p0ozqx2L1U7HZvtsPHdverp7lvskM3u8BYK6vSxCMw2dXK0nzftmVO-dwsH-e3iH9ysFELfX97Z1WS6q-fa8v9Iu5YFBv4phy9_ifgH8BBcCbLQ</recordid><startdate>20060323</startdate><enddate>20060323</enddate><creator>Zhu, Guangyu</creator><creator>Yang, Fanglong</creator><creator>Balachandran, Raghavan</creator><creator>Höök, Peter</creator><creator>Vallee, Richard B</creator><creator>Curran, Dennis P</creator><creator>Day, Billy W</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>20060323</creationdate><title>Synthesis and Biological Evaluation of Purealin and Analogues as Cytoplasmic Dynein Heavy Chain Inhibitors</title><author>Zhu, Guangyu ; Yang, Fanglong ; Balachandran, Raghavan ; Höök, Peter ; Vallee, Richard B ; Curran, Dennis P ; Day, Billy W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-a5bc6b865490b3ea44e9621e8cca25423cc37a31f23442122e2fcd5d06cc93933</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adenosine Triphosphatases - chemistry</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bromobenzenes - chemical synthesis</topic><topic>Bromobenzenes - chemistry</topic><topic>Bromobenzenes - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cytoplasm - enzymology</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Dyneins - antagonists & inhibitors</topic><topic>General aspects</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Porifera</topic><topic>Protein Structure, Tertiary</topic><topic>Rats</topic><topic>Recombinant Proteins - chemistry</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Guangyu</creatorcontrib><creatorcontrib>Yang, Fanglong</creatorcontrib><creatorcontrib>Balachandran, Raghavan</creatorcontrib><creatorcontrib>Höök, Peter</creatorcontrib><creatorcontrib>Vallee, Richard B</creatorcontrib><creatorcontrib>Curran, Dennis P</creatorcontrib><creatorcontrib>Day, Billy W</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><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>Zhu, Guangyu</au><au>Yang, Fanglong</au><au>Balachandran, Raghavan</au><au>Höök, Peter</au><au>Vallee, Richard B</au><au>Curran, Dennis P</au><au>Day, Billy W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Biological Evaluation of Purealin and Analogues as Cytoplasmic Dynein Heavy Chain Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| subjects | Adenosine Triphosphatases - chemistry Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Bromobenzenes - chemical synthesis Bromobenzenes - chemistry Bromobenzenes - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Cytoplasm - enzymology Drug Screening Assays, Antitumor Dyneins - antagonists & inhibitors General aspects Humans Kinetics Medical sciences Mice Pharmacology. Drug treatments Porifera Protein Structure, Tertiary Rats Recombinant Proteins - chemistry Structure-Activity Relationship |
| title | Synthesis and Biological Evaluation of Purealin and Analogues as Cytoplasmic Dynein Heavy Chain Inhibitors |
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