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Citation
Tags
HERO ID
3537651
Reference Type
Journal Article
Title
Total synthesis of the potent anticancer Aglaia metabolites (-)-silvestrol and (-)-episilvestrol and the active analogue (-)-4'-desmethoxyepisilvestrol
Author(s)
Adams, TE; El Sous, M; Hawkins, BC; Hirner, S; Holloway, G; Khoo, ML; Owen, DJ; Savage, GP; Scammells, PJ; Rizzacasa, MA
Year
2009
Is Peer Reviewed?
Yes
Journal
Journal of the American Chemical Society
ISSN:
0002-7863
EISSN:
1520-5126
Book Title
Journal of the American Chemical Society
Volume
131
Issue
4
Page Numbers
1607-1616
Language
English
PMID
19140688
DOI
10.1021/ja808402e
Web of Science Id
WOS:000264791800058
URL
https://pubs.acs.org/doi/10.1021/ja808402e
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Abstract
Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach based on the proposed biosynthesis of these novel compounds. The key steps included an oxidative rearrangement of the protected d-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2]-cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced alpha-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD to afford the axial coupled product 36. Deprotection then gave episilvestrol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4'-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4'-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.
Tags
OPPT REs
•
OPPT_1,4-Dioxane_D. Exposure
Total – title/abstract screening
Supplemental Search
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OPPT_1,4-Dioxane_F. Human Health
Total – title/abstract screening
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