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Synthesis and high content cell-based profiling of simplified analogues of the microtubule stabilizer (+)-discodermolide

Minguez, JM and Giuliano, KA and Balachandran, R and Madiraju, C and Curran, DP and Day, BW (2002) Synthesis and high content cell-based profiling of simplified analogues of the microtubule stabilizer (+)-discodermolide. Molecular Cancer Therapeutics, 1 (14). 1305 - 1313. ISSN 1535-7163

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(+)-Discodermolide, a C24:4, trihydroxylated, octamethyl, carbamate-bearing fatty acid lactone originally isolated from a Caribbean sponge, has proven to be the most potent of the microtubule-stabilizing agents. Recent studies suggest that it or its analogues may have advantages over other classes of microtubule-stabilizing agents. (+)-Discodermolide's complex molecular architecture has made structure-activity relationship analysis in this class of compounds a formidable task. The goal of this study was to prepare simplified analogues of (+)-discodermolide and to analyze their biological activities to expand structure-activity relationships. A small library of analogues was prepared wherein the (+)-discodermolide methyl groups at C-14 and C-16 and the C-7 hydroxyl were removed, and the lactone was replaced by simple esters. The library components were analyzed for microtubule-stabilizing actions in vitro, antiproliferative activity against a small panel of human carcinoma cells, and cell signaling, microtubule architecture and mitotic spindle alterations by a multiparameter fluorescence cell-based screening technique. The results show that even drastic structural simplification can lead to analogues with actions related to microtubule targeting and signal transduction, but that these subtle effects were illuminated only through the high information content cell-based screen. © 2002 American Association for Cancer Research.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Minguez, JM
Giuliano, KA
Balachandran, R
Madiraju, C
Curran, DPcurran@pitt.eduCURRAN
Day, BW
Date: 1 December 2002
Date Type: Publication
Journal or Publication Title: Molecular Cancer Therapeutics
Volume: 1
Number: 14
Page Range: 1305 - 1313
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1535-7163
MeSH Headings: Alkanes; Antineoplastic Agents--pharmacology; Binding Sites; Carbamates; Carbon--chemistry; Carcinoma--pathology; Cell Division; Dose-Response Relationship, Drug; Gene Library; HeLa Cells; Humans; Lactones--pharmacology; Microtubules--drug effects; Microtubules--metabolism; Models, Chemical; Paclitaxel--pharmacology; Phosphorylation; Pyrones; Signal Transduction; Spindle Apparatus; Tubulin--metabolism; Tumor Cells, Cultured
PubMed ID: 12516963
Date Deposited: 12 Feb 2014 23:41
Last Modified: 02 Feb 2019 15:58


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