PMID- 21214226
OWN - NLM
STAT- MEDLINE
DCOM- 20110419
LR  - 20211020
IS  - 1520-6025 (Electronic)
IS  - 0163-3864 (Print)
IS  - 0163-3864 (Linking)
VI  - 74
IP  - 2
DP  - 2011 Feb 25
TI  - Natural and semisynthetic mammea-type isoprenylated dihydroxycoumarins uncouple 
      cellular respiration.
PG  - 240-8
LID - 10.1021/np100762s [doi]
AB  - 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 muM for hypoxia-induced) and PC-3 cells (IC(50) 
      0.94 muM 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.
FAU - Du, Lin
AU  - Du L
AD  - Department of Pharmacognosy, School of Pharmacy, University of Mississippi, 
      University, Mississippi 38677, United States.
FAU - Mahdi, Fakhri
AU  - Mahdi F
FAU - Jekabsons, Mika B
AU  - Jekabsons MB
FAU - Nagle, Dale G
AU  - Nagle DG
FAU - Zhou, Yu-Dong
AU  - Zhou YD
LA  - eng
GR  - R01 CA098787-06/CA/NCI NIH HHS/United States
GR  - C06 RR014503/RR/NCRR NIH HHS/United States
GR  - CA98787/CA/NCI NIH HHS/United States
GR  - C06 RR-14503-01/RR/NCRR NIH HHS/United States
GR  - R01 CA098787/CA/NCI NIH HHS/United States
GR  - R01 CA098787-07/CA/NCI NIH HHS/United States
GR  - R56 CA098787/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110107
PL  - United States
TA  - J Nat Prod
JT  - Journal of natural products
JID - 7906882
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Coumarins)
RN  - 0 (Hypoxia-Inducible Factor 1)
SB  - IM
MH  - Algorithms
MH  - *Antineoplastic Agents, Phytogenic/chemical synthesis/chemistry/isolation & 
      purification/pharmacology
MH  - Cell Respiration/*drug effects
MH  - *Coumarins/chemical synthesis/chemistry/isolation & purification/pharmacology
MH  - Dominica
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*drug effects
MH  - Male
MH  - Mammea/*chemistry
MH  - Molecular Structure
MH  - Plant Bark/chemistry
MH  - Prenylation
MH  - Structure-Activity Relationship
PMC - PMC3045645
MID - NIHMS263677
EDAT- 2011/01/11 06:00
MHDA- 2011/04/20 06:00
PMCR- 2012/02/25
CRDT- 2011/01/11 06:00
PHST- 2011/01/11 06:00 [entrez]
PHST- 2011/01/11 06:00 [pubmed]
PHST- 2011/04/20 06:00 [medline]
PHST- 2012/02/25 00:00 [pmc-release]
AID - 10.1021/np100762s [doi]
PST - ppublish
SO  - J Nat Prod. 2011 Feb 25;74(2):240-8. doi: 10.1021/np100762s. Epub 2011 Jan 7.