Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expression

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Title Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expression
Author Grkovic, Tanja; Whitson, Emily L.; Rabe, Daniel C.; Gardella, Roberta S.; Bottaro, Donald P.; Linehan, W. Marston; McMahon, James B.; Gustafson, Kirk R.; McKee, Tawnya C.
Journal Name Bioorganic & Medicinal Chemistry Letters
Year Published 2011
Place of publication United Kingdom
Publisher Elsevier
Abstract Kidney cancer was the cause of almost 13,000 deaths in the United States in 2009. Loss of function of the VHL tumor suppressor gene (von Hippel–Lindau disease) dramatically increases the risk of developing clear cell kidney cancer. The VHL protein is best understood for its regulation of hypoxia inducible factor (HIF). HIF responds to changes in oxygen levels in the cell and is responsible for mediating the transcriptional response to hypoxia. Of the three known HIFalpha gene products, HIF-2alpha appears to play a fundamental role in renal carcinoma. A high throughput screen was developed to identify small molecule inhibitors of HIF-2 gene expression. The screen was performed and yielded 153 confirmed active natural product extracts. Three of the active extracts were from marine soft corals of the order Alcyonacea: Sarcophyton sp., Lobophytum sarcophytoides and Asterospicularia laurae. Bioassay-guided fractionation led to the isolation of two new cembrane diterpenes, (4Z,8S*,9R*,12E,14E)-9-hydroxy-1-(prop-1-en-2-yl)-8,12-dimethyl-oxabicyclo[9.3.2]-hexadeca-4,12,14-trien-18-one (1), and (1E,3E,7R*,8R*,11E)-1-(2-methoxypropan-2-yl)-4,8,12-trimethyloxabicyclo[12.1.0]-pentadeca-1,3,11-triene (7), as well as eight known compounds, 2–6 and 8–10.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1016/j.bmcl.2011.01.127
Volume 21
Issue Number 7
Page from 2113
Page to 2115
ISSN 0960-894X
Date Accessioned 2011-08-10
Date Available 2011-09-22T06:52:41Z
Language en_AU
Research Centre Eskitis Institute for Drug Discovery
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Biologically Active Molecules
URI http://hdl.handle.net/10072/40966
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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