Molecular-targeted antitumor agents: the Saururus cernuus dineolignans manassantin B and 4-O-demethylmanassantin B are potent inhibitors of hypoxia-activated HIF-1.
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.
Hodges
Tyler W
TW
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.
Hossain
Chowdhury Faiz
CF
Kim
Yong-Pil
YP
Zhou
Yu-Dong
YD
Nagle
Dale G
DG
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005663:Furans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010946:Plants, Medicinal / Q000737:chemistry*; D032134:Saururaceae / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
C486999:4-O-demethylmanassantin B; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D005663:Furans; D051793:Hypoxia-Inducible Factor 1; D017705:Lignans; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C482885:manassantin B