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Synthesis and biological evaluation of purealin and analogues as cytoplasmic dynein heavy chain inhibitors

Zhu, G and Yang, F and Balachandran, R and Höök, P and Vallee, RB and Curran, DP and Day, BW (2006) Synthesis and biological evaluation of purealin and analogues as cytoplasmic dynein heavy chain inhibitors. Journal of Medicinal Chemistry, 49 (6). 2063 - 2076. ISSN 0022-2623

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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. © 2006 American Chemical Society.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Zhu, G
Yang, F
Balachandran, R
Höök, P
Vallee, RB
Curran, DPcurran@pitt.eduCURRAN
Day, BW
Date: 23 March 2006
Date Type: Publication
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 49
Number: 6
Page Range: 2063 - 2076
DOI or Unique Handle: 10.1021/jm051030l
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-2623
MeSH Headings: Adenosine Triphosphatases--chemistry; Animals; Antineoplastic Agents--chemical synthesis; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Bromobenzenes--chemical synthesis; Bromobenzenes--chemistry; Bromobenzenes--pharmacology; Cell Line, Tumor; Cell Proliferation--drug effects; Cytoplasm--enzymology; Drug Screening Assays, Antitumor; Dyneins--antagonists & inhibitors; Humans; Kinetics; Mice; Porifera; Protein Structure, Tertiary; Rats; Recombinant Proteins--chemistry; Structure-Activity Relationship
PubMed ID: 16539395
Date Deposited: 27 Jun 2013 14:54
Last Modified: 02 Feb 2019 15:58


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