Article

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

ABSTRACT

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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    • "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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