PMID- 15165135
OWN - NLM
STAT- MEDLINE
DCOM- 20040624
LR  - 20161124
IS  - 0163-3864 (Print)
IS  - 0163-3864 (Linking)
VI  - 67
IP  - 5
DP  - 2004 May
TI  - Molecular-targeted antitumor agents: the Saururus cernuus dineolignans 
      manassantin B and 4-O-demethylmanassantin B are potent inhibitors of 
      hypoxia-activated HIF-1.
PG  - 767-71
AB  - The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of 
      tumor cell adaptation and survival under hypoxic conditions. Selective HIF-1 
      inhibitors represent an important new class of potential molecular-targeted 
      antitumor therapeutic agents. Extracts of plants and marine organisms were 
      evaluated using a T47D human breast tumor cell-based reporter assay for HIF-1 
      inhibitors. Bioassay-guided fractionation of the lipid extract of Saururus 
      cernuus resulted in the isolation of manassantin B (1) and a new compound, 
      4-O-demethylmanassantin B (2). The structure of 2 was determined 
      spectroscopically. The absolute configurations of manassantin-type dineolignans 
      have not been previously reported. Therefore, the absolute configurations of the 
      chiral centers in each side chain were deduced from spectroscopic analysis of the 
      Mosher MTPA ester derivatives of 1. Both 1 and 2 are among the most potent small 
      molecule HIF-1 inhibitors discovered, to date, with IC(50) values of 3 and 30 nM, 
      respectively. Compounds 1 and 2 selectively inhibited hypoxia-activated HIF-1 in 
      contrast to iron chelator-activated HIF-1. Compounds 1 and 2 also inhibited 
      hypoxic induction of the angiogenic factor VEGF. Further study revealed that 1 
      selectively blocked the induction of HIF-1alpha protein, the oxygen regulated 
      HIF-1 subunit that determines HIF-1 activity.
FAU - Hodges, Tyler W
AU  - Hodges TW
AD  - Department of Pharmacognosy, National Center for Natural Products Research, and 
      Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of 
      Mississippi, University, Mississippi 38677-1848, USA.
FAU - Hossain, Chowdhury Faiz
AU  - Hossain CF
FAU - Kim, Yong-Pil
AU  - Kim YP
FAU - Zhou, Yu-Dong
AU  - Zhou YD
FAU - Nagle, Dale G
AU  - Nagle DG
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Nat Prod
JT  - Journal of natural products
JID - 7906882
RN  - 0 (4-O-demethylmanassantin B)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Furans)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Lignans)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (manassantin B)
SB  - IM
MH  - Antineoplastic Agents, Phytogenic/chemistry/*isolation & 
      purification/*pharmacology
MH  - DNA-Binding Proteins/*antagonists & inhibitors
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Furans/chemistry/*isolation & purification/*pharmacology
MH  - *Hypoxia
MH  - Hypoxia-Inducible Factor 1
MH  - Inhibitory Concentration 50
MH  - Lignans/chemistry/*isolation & purification/*pharmacology
MH  - Nuclear Proteins/*antagonists & inhibitors
MH  - Plants, Medicinal/*chemistry
MH  - Saururaceae/*chemistry
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Transcription Factors/antagonists & inhibitors
MH  - Vascular Endothelial Growth Factor A/analysis
EDAT- 2004/05/29 05:00
MHDA- 2004/06/25 05:00
CRDT- 2004/05/29 05:00
PHST- 2004/05/29 05:00 [pubmed]
PHST- 2004/06/25 05:00 [medline]
PHST- 2004/05/29 05:00 [entrez]
AID - 10.1021/np030514m [doi]
PST - ppublish
SO  - J Nat Prod. 2004 May;67(5):767-71. doi: 10.1021/np030514m.