title: Natural and semisynthetic mammea-type isoprenylated dihydroxycoumarins uncouple cellular respiration.
abstract: In an effort to identify natural product-based molecular-targeted antitumor agents, mammea-type coumarins from the tropical/subtropical plant Mammea americana were found to inhibit the activation of HIF-1 (hypoxia-inducible factor-1) in human breast and prostate tumor cells. In addition to the recently reported mammea E/BB (15), bioassay-guided fractionation of the active extract yielded 14 mammea-type coumarins including three new compounds, mammea F/BB (1), mammea F/BA (2), and mammea C/AA (3). The absolute configuration of C-1' in 1 was determined by the modified Mosher's method on a methylated derivative. These coumarins were evaluated for their effects on mitochondrial respiration, HIF-1 signaling, and tumor cell proliferation/viability. Acetylation of 1 afforded a triacetoxylated product (A-2) that inhibited HIF-1 activation with increased potency in both T47D (IC(50) 0.83 μM for hypoxia-induced) and PC-3 cells (IC(50) 0.94 μM for hypoxia-induced). Coumarins possessing a 6-prenyl-8-(3-methyloxobutyl) substituent pattern exhibited enhanced HIF-1 inhibitory effects. The O-methylated derivatives were less active at inhibiting HIF-1 and suppressing cell proliferation/viability. Mechanistic studies indicate that these compounds act as anionic protonophores that potently uncouple mitochondrial electron transport and disrupt hypoxic signaling.
authors.affiliation: Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: Mika B
authors.initials: MB
authors.lastname: Jekabsons
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
mesh_terms: D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D019424:Dominica; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects*; D008297:Male; D031252:Mammea / Q000737:chemistry*; D015394:Molecular Structure; D024301:Plant Bark / Q000737:chemistry; D054876:Prenylation; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D051793:Hypoxia-Inducible Factor 1