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Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents

Choy, N and Shin, Y and Nguyen, PQ and Curran, DP and Balachandran, R and Madiraju, C and Day, BW (2003) Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. Journal of Medicinal Chemistry, 46 (14). 2846 - 2864. ISSN 0022-2623

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Abstract

Several novel analogues of (+)-discodermolide were synthesized via a convergent strategy that used Wittig reactions to append left and right side chains to a central scaffold and then tested for biological activity. Three of the analogues in the 4-epi-7-dehydroxy-14,16-didemethyl series, 6a-c, had interesting actions. The C3-methoxymethyl ether analogue 6b was more active in antiproliferative cell-based assays as well as in hypernucleation and paclitaxel site competition assays with isolated tubulin than the other analogues, including 6a, which contained a free hydroxyl group at the C3 position. The biological results validated the initial hypothesis that the C7 hydroxy group and the C14 and C16 methyl groups of (+)-discodermolide could be deleted without undermining activity. Although less potent than (+)-discodermolide and paclitaxel, compounds 6b and 6c both showed properties unique to (+)-discodermolide. These properties, particularly the capacity to cause hypernucleation of isolated tubulin at lower temperature than paclitaxel, as well as stabilizing preformed microtubules to cold disassembly, are considered mechanistically superior to those of paclitaxel. Other variations in the right and left sides of the discodermolide scaffold revealed additional structure/activity information.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Choy, N
Shin, Y
Nguyen, PQ
Curran, DPcurran@pitt.eduCURRAN
Balachandran, R
Madiraju, C
Day, BW
Date: 3 July 2003
Date Type: Publication
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 46
Number: 14
Page Range: 2846 - 2864
DOI or Unique Handle: 10.1021/jm0204136
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-2623
MeSH Headings: Alkanes; Animals; Antineoplastic Agents--chemical synthesis; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Binding Sites; Binding, Competitive; Carbamates; Cattle; Cell Division--drug effects; Crystallography, X-Ray; Lactones--chemical synthesis; Lactones--chemistry; Lactones--pharmacology; Microtubules--drug effects; Paclitaxel--chemistry; Paclitaxel--pharmacology; Pyrones; Stereoisomerism; Structure-Activity Relationship; Tubulin--chemistry
PubMed ID: 12825928
Date Deposited: 06 Feb 2014 23:56
Last Modified: 02 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/20477

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