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

• Published in: Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (7), p.2113-2115
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Alcyonacea; Alcyonaceae; Animals; Anthozoa - chemistry; Asterospicularia laurae; Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors; Basic Helix-Loop-Helix Transcription Factors - physiology; Bioassay-guided fractionation; Biological and medical sciences; carcinoma; Cembrane; Clear cells; Corals; diterpenes; Diterpenes - analysis; diterpenoids; fractionation; Gene expression; General pharmacology; HIF; Hypoxia; kidney neoplasms; Lobophytum; Lobophytum sarcophytoides; Magnetic Resonance Spectroscopy; Marine natural products; Medical sciences; natural products; Oxygen; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Renal carcinoma; renal cell carcinoma; risk; Sarcophyton; Sarcophyton sp; Soft coral; Spectrometry, Mass, Electrospray Ionization; Transcription; transcription (genetics); tumor suppressor genes; VHL protein; Von Hippel-Lindau disease
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.127

Two new cembrane diterpenes, (4 Z,8 S*,9 R*,12 E,14 E)-9-hydroxy-1-(prop-1-en-2-yl)-8,12-dimethyl-oxabicyclo[9.3.2]-hexadeca-4,12,14-trien-18-one ( 1), and (1 E,3 E,7 R*,8 R*,11 E)-1-(2-methoxypropan-2-yl)-4,8,12-trimethyl-oxabicyclo[12.1.0]-pentadeca-1,3,11-triene ( 7), as well as eight known compounds, 2– 6 and 8– 10 were isolated. 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 HIFα gene products, HIF-2α 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, (4 Z,8 S*,9 R*,12 E,14 E)-9-hydroxy-1-(prop-1-en-2-yl)-8,12-dimethyl-oxabicyclo[9.3.2]-hexadeca-4,12,14-trien-18-one ( 1), and (1 E,3 E,7 R*,8 R*,11 E)-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.