eprintid: 20477
rev_number: 16
userid: 1418
dir: disk0/00/02/04/77
datestamp: 2014-02-06 23:56:58
lastmod: 2019-02-02 15:58:38
status_changed: 2014-02-06 23:56:58
type: article
metadata_visibility: show
item_issues_count: 0
eprint_status: archive
creators_name: Choy, N
creators_name: Shin, Y
creators_name: Nguyen, PQ
creators_name: Curran, DP
creators_name: Balachandran, R
creators_name: Madiraju, C
creators_name: Day, BW
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creators_email: curran@pitt.edu
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creators_id: 
creators_id: 
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creators_id: CURRAN
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title: Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents
ispublished: pub
divisions: sch_as_chemistry
full_text_status: public
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.
date: 2003-07-03
date_type: published
publication: Journal of Medicinal Chemistry
volume: 46
number: 14
pagerange: 2846 - 2864
refereed: TRUE
issn: 0022-2623
id_number: 10.1021/jm0204136
pmid: 12825928
mesh_headings: Alkanes
mesh_headings: Animals
mesh_headings: Antineoplastic Agents--chemical synthesis
mesh_headings: Antineoplastic Agents--chemistry
mesh_headings: Antineoplastic Agents--pharmacology
mesh_headings: Binding Sites
mesh_headings: Binding, Competitive
mesh_headings: Carbamates
mesh_headings: Cattle
mesh_headings: Cell Division--drug effects
mesh_headings: Crystallography, X-Ray
mesh_headings: Lactones--chemical synthesis
mesh_headings: Lactones--chemistry
mesh_headings: Lactones--pharmacology
mesh_headings: Microtubules--drug effects
mesh_headings: Paclitaxel--chemistry
mesh_headings: Paclitaxel--pharmacology
mesh_headings: Pyrones
mesh_headings: Stereoisomerism
mesh_headings: Structure-Activity Relationship
mesh_headings: Tubulin--chemistry
chemical_names: Alkanes
chemical_names: Antineoplastic Agents
chemical_names: Carbamates
chemical_names: Lactones
chemical_names: Pyrones
chemical_names: Tubulin
chemical_names: Paclitaxel
chemical_names: discodermolide
citation:   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     
document_url: http://d-scholarship-dev.library.pitt.edu/20477/1/licence.txt