Laurenditerpenol, a new diterpene from the tropical marine alga Laurenciaintricata that potently inhibits HIF-1 mediated hypoxic signaling in breast tumor cells.

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.

• Authors: Kaleem A Mohammed, Chowdhury Faiz Hossain, Lei Zhang, Richard K Bruick, Yu-Dong Zhou, Dale G Nagle
• Journal: Journal of natural products (J Nat Prod) Vol. 67 Issue 12 Pg. 2002-7 (Dec 2004) ISSN: 0163-3864 [Print] United States
• PMID: 15620241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• Diterpenes
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Transcription Factors
• laurenditerpenol

Topics

• Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
• Breast Neoplasms
• DNA-Binding Proteins (antagonists & inhibitors)
• Diterpenes (chemistry, isolation & purification, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mitochondria (metabolism)
• Molecular Structure
• Nuclear Magnetic Resonance, Biomolecular
• Nuclear Proteins (antagonists & inhibitors)
• Rhodophyta (chemistry)
• Stereoisomerism
• Transcription Factors (antagonists & inhibitors)