Zhu, W and Jiménez, M and Jung, WH and Camarco, DP and Balachandran, R and Vogt, A and Day, BW and Curran, DP
(2010)
Streamlined syntheses of (-)-dictyostatin, 16-desmethyl-25,26- dihydrodictyostatin, and 6- epi -16-desmethyl-25,26-dihydrodictyostatin.
Journal of the American Chemical Society, 132 (26).
9175 - 9187.
ISSN 0002-7863
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Abstract
The dictyostatins are a promising class of potential anti-cancer drugs because they are powerful microtubule-stabilizing agents, but the complexity of their chemical structures is a severe impediment to their further development. On the basis of both synthetic and medicinal chemistry analyses, 16-desmethyl-25,26-dihydrodictyostatin and its C6 epimer were chosen as potentially potent yet accessible dictyostatin analogues, and three new syntheses were developed. A relatively classical synthesis involving vinyllithium addition and macrocyclization gave way to a newer and more practical approach based on esterification and ring-closing metathesis reaction. Finally, aspects of these two approaches were combined to provide a third new synthesis based on esterification and Nozaki-Hiyama-Kishi reaction. This was used to prepare the target dihydro analogues and the natural product. All of the syntheses are streamlined because of their high convergency. The work provided several new analogues of dictyostatin, including a truncated macrolactone and a C10 E-alkene, which were 400- and 50-fold less active than (-)-dictyostatin, respectively. In contrast, the targeted 16-desmethyl-25,26-dihydrodictyostatin analogues retained almost complete activity in preliminary biological assays. © 2010 American Chemical Society.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
---|
Zhu, W | | | | Jiménez, M | | | | Jung, WH | | | | Camarco, DP | | | | Balachandran, R | | | | Vogt, A | | | | Day, BW | | | | Curran, DP | curran@pitt.edu | CURRAN | |
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Date: |
7 July 2010 |
Date Type: |
Publication |
Journal or Publication Title: |
Journal of the American Chemical Society |
Volume: |
132 |
Number: |
26 |
Page Range: |
9175 - 9187 |
DOI or Unique Handle: |
10.1021/ja103537u |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
0002-7863 |
MeSH Headings: |
Carbon--chemistry; Cell Line, Tumor; Cell Proliferation--drug effects; Esterification; Humans; Lactones--chemistry; Lithium--chemistry; Macrolides--chemical synthesis; Macrolides--chemistry; Macrolides--pharmacology |
Other ID: |
NLM NIHMS214066, NLM PMC2903049 |
PubMed Central ID: |
PMC2903049 |
PubMed ID: |
20545347 |
Date Deposited: |
08 Feb 2013 20:46 |
Last Modified: |
04 Feb 2019 15:57 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/17295 |
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