Laurenditerpenol, a New Diterpene from the Tropical Marine Alga Laurencia i ntricata that Potently Inhibits HIF-1 Mediated Hypoxic Signaling in Breast Tumor Cells

Biochemistry, University of Texas at Dallas, Richardson, Texas, United States
Journal of Natural Products (Impact Factor: 3.8). 01/2005; 67(12):2002-7. DOI: 10.1021/np049753f
Source: PubMed


The degree of tumor hypoxia correlates with advanced disease stages and treatment resistance. The transcription factor hypoxia-inducible factor-1 (HIF-1) promotes tumor cell adaptation and survival under hypoxic conditions. Therefore, specific HIF-1 inhibitors represent an important new class of potential tumor-selective therapeutic agents. A T47D human breast tumor cell-based reporter assay was used to examine extracts of plants and marine organisms for inhibitors of HIF-1 activation. Bioassay-guided fractionation of the lipid extract of the red alga Laurencia intricata yielded a structurally novel diterpene, laurenditerpenol (1). The structure of 1 was determined spectroscopically. The relative configurations of the substituents of each ring system were assigned on the basis of NOESY correlations. The absolute configuration of position C-1 was determined by the modified Mosher ester procedure (directly in NMR tubes). Compound 1 potently inhibited hypoxia-activated HIF-1 (IC50: 0.4 microM) and hypoxia-induced VEGF (a potent angiogenic factor) in T47D cells. Compound 1 selectively inhibits HIF-1 activation by hypoxia but not iron chelator-induced activation. Further, 1 suppresses tumor cell survival under hypoxic conditions without affecting normoxic cell growth. Compound 1 inhibits HIF-1 by blocking the induction of the oxygen-regulated HIF-1alpha protein. Mitochondrial respiration studies revealed that 1 suppresses oxygen consumption.

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    • "This screening has also confirmed the great bioactivity of species in the Ceramiales, especially B. byssoides, which had cytotoxic activities against all human cancer cell lines tested. Numerous cytotoxic compounds have been isolated previously from species of Ceramiales, especially from the genus Laurencia (e.g., Pec et al. 2003, Mohammed et al. 2004, Sun et al. 2005 "
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    Botanica Marina 06/2009; 52(3):268-277. DOI:10.1515/BOT.2009.037 · 1.40 Impact Factor
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    • "Using a T47D human breast tumor cell-based luciferase reporter assay to monitor HIF-1 activity, extracts from more than two thousand plants and marine organisms were evaluated for HIF-1 inhibitory activity (Hodges et al., 2004; Mohammed et al., 2004). Bioassay-guided fractionation of the lipid extract of a Jamaican collection of the red alga Laurencia intricata Lamouroux (Rhodomelaceae) yielded the first marine natural product that inhibited HIF-1 activation (Mohammed et al., 2004). The active compound was a structurally novel bicyclic diterpene called laurenditerpenol (1) that inhibited hypoxia (1% O 2 )-induced HIF-1 activation in T47D cells (IC 50 0.4 μM). "
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