title: 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: Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS 38677, United States.
authors: Jun
authors: J
authors: Li
authors: Fakhri
authors: F
authors: Mahdi
authors: Lin
authors: L
authors: Du
authors: Mika B
authors: MB
authors: Jekabsons
authors: Yu-Dong
authors: YD
authors: Zhou
authors: Dale G
authors: DG
authors: Nagle
mesh_terms: D045471:Aegle / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity*; D019587:Dietary Supplements / Q000009:adverse effects / Q000032:analysis; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010936:Plant Extracts / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D051793:Hypoxia-Inducible Factor 1; D010936:Plant Extracts; C105832:aurapten