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Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin

Jung, WH and Harrison, C and Shin, Y and Fournier, JH and Balachandran, R and Raccor, BS and Sikorski, RP and Vogt, A and Curran, DP and Day, BW (2007) Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin. Journal of Medicinal Chemistry, 50 (13). 2951 - 2966. ISSN 0022-2623

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Abstract

The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16- dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16- dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents. © 2007 American Chemical Society.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Jung, WH
Harrison, C
Shin, Y
Fournier, JH
Balachandran, R
Raccor, BS
Sikorski, RP
Vogt, A
Curran, DPcurran@pitt.eduCURRAN
Day, BW
Date: 28 June 2007
Date Type: Publication
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 50
Number: 13
Page Range: 2951 - 2966
DOI or Unique Handle: 10.1021/jm061385k
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-2623
MeSH Headings: Animals; Antineoplastic Agents--chemical synthesis; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Binding, Competitive; Cattle; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Macrolides--chemical synthesis; Macrolides--chemistry; Macrolides--pharmacology; Microtubules--chemistry; Stereoisomerism; Structure-Activity Relationship; Tubulin--chemistry
PubMed ID: 17542572
Date Deposited: 08 Apr 2013 17:08
Last Modified: 02 Feb 2019 16:56
URI: http://d-scholarship.pitt.edu/id/eprint/18236

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