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Synthesis and biological assessment of simplified analogues of the potent microtubule stabilizer (+)-discodermolide

Mínguez, JM and Kim, SY and Giuliano, KA and Balachandran, R and Madiraju, C and Day, BW and Curran, DP (2003) Synthesis and biological assessment of simplified analogues of the potent microtubule stabilizer (+)-discodermolide. Bioorganic and Medicinal Chemistry, 11 (15). 3335 - 3357. ISSN 0968-0896

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Abstract

An efficient, convergent and stereocontrolled synthesis of simplified analogues of the potent antimitotic agent (+)-discodermolide has been achieved and several small libraries have been prepared. In all the libraries, the discodermolide methyl groups at C14 and C16 and the C7 hydroxy group were removed and the lactone was replaced by simple esters. Other modifications introduced in each series of analogues were related to C11, C17 and C19 of the natural product. Key elements of the synthetic strategy included (a) elaboration of the main subunits from a common intermediate and (b) fragment couplings using Wittig reactions to install the (Z)-olefins. Library components were analyzed for microtubule-stabilizing actions in vitro, for displacement of [3H]paclitaxel from its binding site on tubulin, for antiproliferative activity against human carcinoma cells, and for cell signaling and mitotic spindle alterations by a multiparameter fluorescence cell-based screening technique. The results show that even significant structural simplification can lead to analogues with actions related to microtubule targeting. © 2003 Elsevier Science Ltd. All rights reserved.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Mínguez, JM
Kim, SY
Giuliano, KA
Balachandran, R
Madiraju, C
Day, BW
Curran, DPcurran@pitt.eduCURRAN
Date: 31 July 2003
Date Type: Publication
Journal or Publication Title: Bioorganic and Medicinal Chemistry
Volume: 11
Number: 15
Page Range: 3335 - 3357
DOI or Unique Handle: 10.1016/s0968-0896(03)00186-x
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0968-0896
MeSH Headings: Alkanes--chemistry; Alkanes--pharmacology; Carbamates--chemistry; Carbamates--pharmacology; Cell Line, Tumor; Humans; Lactones--chemistry; Lactones--pharmacology; Microtubules--drug effects; Microtubules--physiology; Pyrones
PubMed ID: 12837544
Date Deposited: 07 Feb 2014 00:00
Last Modified: 05 Feb 2019 03:55
URI: http://d-scholarship.pitt.edu/id/eprint/20478

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