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

  1. Author:
    Grkovic, T.
    Whitson, E. L.
    Rabe, D. C.
    Gardella, R. S.
    Bottaro, D. P.
    Linehan, W. M.
    McMahon, J. B.
    Gustafson, K. R.
    McKee, T. C.

  2. Author Address

    [Grkovic, Tanja; Whitson, Emily L.; Gardella, Roberta S.; McMahon, James B.; Gustafson, Kirk R.; McKee, Tawnya C.] NCI, Mol Targets Lab, Frederick, MD 21702 USA. [Rabe, Daniel C.; Bottaro, Donald P.; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Gardella, Roberta S.] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA.;McKee, TC, NCI, Mol Targets Lab, Frederick, MD 21702 USA.;mckeeta@mail.nih.gov
    1. Year: 2011
    2. Date: Apr
  2. Journal: Bioorganic & Medicinal Chemistry Letters
    1. 21
    2. 7
    3. Pages: 2113-2115
  4. Type of Article: Article
  5. ISSN: 0960-894X
  1. 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 HIF alpha gene products, HIF-2 alpha 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]-hexade ca-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]-pentade ca-1,3,11-triene (7), as well as eight known compounds, 2-6 and 8-10. (C) 2011 Elsevier Ltd. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.bmcl.2011.01.127
  3. View record in Web of Science®
  4. WOS: 000288245100044

Library Notes

  1. Fiscal Year: FY2010-2011
NCI at Frederick

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