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Cellular analysis of disorazole C<inf>1</inf> and structure-activity relationship of analogs of the natural product

Wipf, P and Graham, TH and Vogt, A and Sikorski, RP and Ducruet, AP and Lazo, JS (2006) Cellular analysis of disorazole C<inf>1</inf> and structure-activity relationship of analogs of the natural product. Chemical Biology and Drug Design, 67 (1). 66 - 73. ISSN 1747-0277

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Structure-activity analyses of synthetic disorazole C1 and eight of its analogs indicate that the presence of a vinyl oxirane moiety or a tetraene sequence is not necessary for potent cytotoxic and antimitotic properties. Using an automated multiparameter fluorescence-based cellular assay to simultaneously probe the effects of disorazole analogs on cellular microtubules, mitotic arrest, and cytotoxicity, we found that disorazole C 1 enhanced the mitotic index and chromatin condensation and arrested cells in the G2/M phase of the cell cycle. All structural analogs and synthesis precursors of disorazole C1 were at least two orders of magnitude less potent than the parent compound, thus indicating that both the functional group array and the three-dimensional conformation of the parent compound are critical for interaction with the biological target. We conclude that disorazole C1 is a potent inducer of mitotic arrest and hypothesize that this biological activity may be mediated by microtubule perturbation. © 2005 Blackwell Munksgaard.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wipf, Ppwipf@pitt.eduPWIPF
Graham, TH
Vogt, A
Sikorski, RP
Ducruet, AP
Lazo, JS
Date: 20 June 2006
Date Type: Publication
Journal or Publication Title: Chemical Biology and Drug Design
Volume: 67
Number: 1
Page Range: 66 - 73
DOI or Unique Handle: 10.1111/j.1747-0285.2005.00313.x
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1747-0277
MeSH Headings: Antimitotic Agents--chemistry; Antimitotic Agents--metabolism; Antimitotic Agents--pharmacology; Biological Agents--chemistry; Biological Agents--metabolism; Biological Agents--pharmacology; Cell Cycle--drug effects; Dose-Response Relationship, Drug; Flow Cytometry; Fluorescent Antibody Technique; HeLa Cells; Humans; Macrolides; Microtubules--drug effects; Mitosis--drug effects; Oxazoles--chemistry; Oxazoles--metabolism; Oxazoles--pharmacology; Oxazoles--toxicity; Structure-Activity Relationship
PubMed ID: 16492150
Date Deposited: 30 Oct 2013 16:52
Last Modified: 22 Jun 2021 12:55


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