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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    • "Several marine natural products, including the diterpenoid laurenditerpenol (11) isolated from the tropical alga Laurencia intricata [127], the triterpenoids sodwanone A (12) and yardenone A (13) isolated from the South African sponge Axinella sp. [128], norsesterterpene peroxides from the marine sponge Diacarnus levii [125], various benzochromenones isolated from the marine crinoid Comantheria rotula [129], the phenolic pyrrole 7-hydroxyneolamellarin A (14) isolated from the sponge Dendrilla nigra [130], various strongylophorines isolated from the sponge Petrosia (Strongylophora) strongylata [131], and the macrolide latrunculin A (15) isolated from the Red Sea sponge Negombata magnifica [132] have been reported as HIF-1 inhibitors. "
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    ABSTRACT: NF-κB is an inducible transcription factor found in virtually all types of vertebrate cells, as well as in some invertebrate cells. While normal activation of NF-κB is required for cell survival and immunity, its deregulated expression is characteristic of cancer, inflammation, and numerous other diseases. Hence, NF-κB has recently become one of the major targets in drug discovery. Several marine organisms use NF-κB (or analogues thereof), NF-κB inducers, or NF-κB inhibitors as chemical defence mechanisms, for parasitic invasion, for symbiosis, or for larval development. In particular, a wide range of marine natural products have been reported to possess NF-κB inhibitory properties, and some of these marine metabolites are currently in clinical trials as anticancer or anti-inflammatory drugs. In the present review, we discuss the role of NF-κB inhibitors in marine chemical ecology, as well as in biomedicine. We also describe synthetic modifications that have been made to a range of highly promising marine NF-κB inhibitors, including the macrolide bryostatin 1 isolated from the bryozoan Bugula neritina, the lactone-γ-lactam salinosporamide A isolated from the actinomycete Salinispora tropica, the alkaloid hymenialdisine isolated from various sponges, the sesquiterpenoid hydroquinone avarol isolated from the sponge Dysidea avara, and the sesterterpene lactone cacospongonolide B isolated from the sponge Fasciospongia cavernosa, to increase their bioactivity and bioavailability, to decrease their level of toxicity or to lower the risk of other detrimental side-effects, and to increase the sustainability of their pharmaceutical production by facilitating their chemical synthesis.
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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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    • "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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