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J Nat Prod. 2009 Nov;72(11):1927-36.

Lipophilic 2,5-disubstituted pyrroles from the marine sponge Mycale sp. inhibit mitochondrial respiration and HIF-1 activation.

Mao SC, Liu Y, Morgan JB, Jekabsons MB, Zhou YD, Nagle DG.

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Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.

Abstract

The lipid extract of the marine sponge Mycale sp. inhibited the activation of hypoxia-inducible factor-1 (HIF-1) in a human breast tumor T47D cell-based reporter assay. Bioassay-guided isolation and structure elucidation yielded 18 new lipophilic 2,5-disubstituted pyrroles and eight structurally related known compounds. The active compounds inhibited hypoxia-induced HIF activation with moderate potency (IC50 values <10 microM). Mechanistic studies revealed that the active compounds suppressed mitochondrial respiration by blocking NADH-ubiquinone oxidoreductase (complex I) at concentrations that inhibited HIF-1 activation. Under hypoxic conditions, reactive oxygen species produced by mitochondrial complex III are believed to act as a signal of cellular hypoxia that leads to HIF-1alpha protein induction and activation. By inhibiting electron transport (or delivery) to complex III under hypoxic conditions, lipophilic Mycale pyrroles appear to disrupt mitochondrial ROS-regulated HIF-1 signaling.

PMID:: 19845338; [PubMed - indexed for MEDLINE]
PMCID:: PMC2868385

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