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

Kaleem A. Mohammed, Chowdhury Faiz Hossain, Lei Zhang, Richard K. Bruick, Yu Dong Zhou, Dale G. Nagle

Research output: Contribution to journalArticle

65 Citations (Scopus)

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 intricate, 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 μM) 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-1α protein. Mitochondrial respiration studies revealed that 1 suppresses oxygen consumption.

Original languageEnglish (US)
Pages (from-to)2002-2007
Number of pages6
JournalJournal of Natural Products
Volume67
Issue number12
DOIs
StatePublished - Dec 2004

Fingerprint

algae
Laurencia
Hypoxia-Inducible Factor 1
Diterpenes
Algae
diterpenoids
breast neoplasms
Tumors
Cells
Breast Neoplasms
hypoxia
Chemical activation
anaerobic conditions
Cell Survival
Oxygen
Rhodophyta
Aquatic Organisms
Neoplasms
neoplasms
Bioassay

ASJC Scopus subject areas

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Laurenditerpenol, a new diterpene from the tropical marine alga Laurencia intricata that potently inhibits HIF-1 mediated hypoxic signaling in breast tumor cells. / Mohammed, Kaleem A.; Hossain, Chowdhury Faiz; Zhang, Lei; Bruick, Richard K.; Zhou, Yu Dong; Nagle, Dale G.

In: Journal of Natural Products, Vol. 67, No. 12, 12.2004, p. 2002-2007.

Research output: Contribution to journalArticle

Mohammed, Kaleem A. ; Hossain, Chowdhury Faiz ; Zhang, Lei ; Bruick, Richard K. ; Zhou, Yu Dong ; Nagle, Dale G. / Laurenditerpenol, a new diterpene from the tropical marine alga Laurencia intricata that potently inhibits HIF-1 mediated hypoxic signaling in breast tumor cells. In: Journal of Natural Products. 2004 ; Vol. 67, No. 12. pp. 2002-2007.
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