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Synthesis and biological evaluation of structurally highly modified analogues of the antimitotic natural product curacin A

Wipf, P and Reeves, JT and Balachandran, R and Day, BW (2002) Synthesis and biological evaluation of structurally highly modified analogues of the antimitotic natural product curacin A. Journal of Medicinal Chemistry, 45 (9). 1901 - 1917. ISSN 0022-2623

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Abstract

Structure-activity relationship analysis of synthetic analogues of curacin A revealed the lack of activity of traditional heterocyclic replacements of the thiazoline ring or cyclopropyl analogues of the core diene segment. The significance of the C(3)-C(4)-(Z)-alkene geometry was established, and a novel oxime analogue was designed that displays biological properties that are a close match of the natural product lead. The much less lipophilic, structurally simplified oxime 50 was only slightly weaker at inhibiting the growth of cultured human tumor cells than the natural product and was found to be more potent than curacin A at inhibiting the assembly of purified tubulin. Accordingly, the oxime moiety is likely to serve as a novel bioisostere of the (Z)-alkene group.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wipf, Ppwipf@pitt.eduPWIPF
Reeves, JT
Balachandran, R
Day, BW
Date: 25 April 2002
Date Type: Publication
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 45
Number: 9
Page Range: 1901 - 1917
DOI or Unique Handle: 10.1021/jm0105171
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-2623
MeSH Headings: Antineoplastic Agents--chemical synthesis; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Biopolymers; Blood Proteins--metabolism; Cell Division--drug effects; Cyclopropanes--chemistry; Cyclopropanes--pharmacology; Drug Screening Assays, Antitumor; Humans; Oximes--chemical synthesis; Oximes--chemistry; Oximes--pharmacology; Protein Binding; Stereoisomerism; Structure-Activity Relationship; Thiazoles--chemistry; Thiazoles--pharmacology; Thiophenes--chemical synthesis; Thiophenes--chemistry; Thiophenes--pharmacology; Tubulin--chemistry; Tumor Cells, Cultured
PubMed ID: 11960501
Date Deposited: 12 Feb 2014 23:42
Last Modified: 24 Jan 2019 05:55
URI: http://d-scholarship.pitt.edu/id/eprint/20455

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