Lipophilic 2,5-disubstituted pyrroles from the marine sponge Mycale sp. inhibit mitochondrial respiration and HIF-1 activation.
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.
Mao
Shui-Chun
SC
Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Liu
Yang
Y
Morgan
J Brian
JB
Jekabsons
Mika B
MB
Zhou
Yu-Dong
YD
Nagle
Dale G
DG
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008386:Marine Biology; D008928:Mitochondria / Q000378:metabolism*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D019029:Palau; D011161:Porifera / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
D051793:Hypoxia-Inducible Factor 1; D011758:Pyrroles