Semisynthetic studies identify mitochondria poisons from botanical dietary supplements--geranyloxycoumarins from Aegle marmelos.

Abstract

Bioassay-guided isolation and subsequent structure elucidation of a Bael tree Aegle marmelos lipid extract yielded two unstable acylated geranyloxycoumarin mixtures (1-2), six geranyloxycoumarins (3-8), (+)-9'-isovaleroxylariciresinol (9), and dehydromarmeline (10). In a T47D cell-based reporter assay, 1 and 2 potently inhibited hypoxia-induced HIF-1 activation (IC50 values 0.18 and 1.10 μgmL(-1), respectively). Insufficient material and chemical instability prevented full delineation of the fatty acyl side chain olefin substitution patterns in 1 and 2. Therefore, five fatty acyl geranyloxycoumarin ester derivatives (11-15) were prepared from marmin (3) and commercial fatty acyl chlorides by semisynthesis. The unsaturated C-6' linoleic acid ester derivative 14 that was structurally most similar to 1 and 2, inhibited HIF-1 activation with comparable potency (IC50 0.92 μM). The octanoyl (11) and undecanoyl (12) ester derivatives also suppressed HIF-1 activation (IC50 values 3.1 and 0.87 μM, respectively). Mechanistic studies revealed that these geranyloxycoumarin derivatives disrupt mitochondrial respiration, primarily at complex I. Thus, these compounds may inhibit HIF-1 activation by suppressing mitochondria-mediated hypoxic signaling. One surprising observation was that, while less potent, the purported cancer chemopreventive agent auraptene (8) was found to act as a mitochondrial poison that disrupts HIF-1 signaling in tumors.

• Authors: Jun Li, Fakhri Mahdi, Lin Du, Mika B Jekabsons, Yu-Dong Zhou, Dale G Nagle
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 7 Pg. 1795-803 (Apr 01 2013) ISSN: 1464-3391 [Electronic] England
• PMID: 23434131 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Coumarins
• Hypoxia-Inducible Factor 1
• Plant Extracts
• aurapten

Topics

• Aegle (chemistry)
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology, toxicity)
• Breast (drug effects, pathology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Respiration (drug effects)
• Cell Survival (drug effects)
• Coumarins (chemistry, isolation & purification, pharmacology, toxicity)
• Dietary Supplements (adverse effects, analysis)
• Female
• Humans
• Hypoxia-Inducible Factor 1 (antagonists & inhibitors, metabolism)
• Mitochondria (drug effects, metabolism, pathology)
• Plant Extracts (chemistry, isolation & purification, pharmacology, toxicity)