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Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin

Madiraju, C and Edler, MC and Hamel, E and Raccor, BS and Balachandran, R and Zhu, G and Giuliano, KA and Vogt, A and Shin, Y and Fournier, JH and Fukui, Y and Brückner, AM and Curran, DP and Day, BW (2005) Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin. Biochemistry, 44 (45). 15053 - 15063. ISSN 0006-2960

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(-)-Dictyostatin is a sponge-derived, 22-member macrolactone natural product shown to cause cells to accumulate in the G2/M phase of the cell cycle, with changes in intracellular microtubules analogous to those observed with paclitaxel treatment. Dictyostatin also induces assembly of purified tubulin more rapidly than does paclitaxel, and nearly as vigorously as does dictyostatin's close structural congener, (+)-discodermolide (Isbrucker et al, (2003), Biochem. Pharmacol 65, 75-82). We used synthetic (-)-dictyostatin to study its biochemical and cytological activities in greater detail. The antiproliferative activity of dictyostatin did not differ greatly from that of paclitaxel or discodermolide. Like discodermolide, dictyostatin retained antiproliferative activity against human ovarian carcinoma cells resistant to paclitaxel due to β-tubulin mutations and caused conversion of cellular soluble tubulin pools to microtubules. Detailed comparison of the abilities of dictyostatin and discodermolide to induce tubulin assembly demonstrated that the compounds had similar potencies. Dictyostatin inhibited the binding of radiolabeled discodermolide to microtubules more potently than any other compound examined, and dictyostatin and discodermolide had equivalent activity as inhibitors of the binding of both radiolabeled epothilone B and paclitaxel to microtubules. These results are consistent with the idea that the macrocyclic structure of dictyostatin represents the template for the bioactive conformation of discodermolide. © 2005 American Chemical Society.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Madiraju, C
Edler, MC
Hamel, E
Raccor, BS
Balachandran, R
Zhu, G
Giuliano, KA
Vogt, A
Shin, Y
Fournier, JH
Fukui, Y
Brückner, AM
Curran, DPcurran@pitt.eduCURRAN
Day, BW
Date: 15 November 2005
Date Type: Publication
Journal or Publication Title: Biochemistry
Volume: 44
Number: 45
Page Range: 15053 - 15063
DOI or Unique Handle: 10.1021/bi050685l
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0006-2960
MeSH Headings: Alkanes--pharmacology; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Binding Sites; Carbamates--pharmacology; Cell Line, Tumor; Cell Proliferation--drug effects; Humans; Lactones--pharmacology; Macrolides--chemistry; Macrolides--pharmacology; Microscopy, Fluorescence; Microtubules--drug effects; Microtubules--ultrastructure; Paclitaxel--pharmacology; Pyrones--pharmacology; Tubulin--metabolism
PubMed ID: 16274252
Date Deposited: 15 Jul 2013 19:54
Last Modified: 02 Feb 2019 15:58


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