relation: http://d-scholarship-dev.library.pitt.edu/20492/
title: Synthesis and high content cell-based profiling of simplified analogues of the microtubule stabilizer (+)-discodermolide
creator: Minguez, JM
creator: Giuliano, KA
creator: Balachandran, R
creator: Madiraju, C
creator: Curran, DP
creator: Day, BW
description: (+)-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.
date: 2002-12-01
type: Article
type: PeerReviewed
format: text/plain
language: en
rights: attached
identifier: http://d-scholarship-dev.library.pitt.edu/20492/1/licence.txt
identifier:   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