Saururus cernuus lignans--potent small molecule inhibitors of hypoxia-inducible factor-1.
Hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective therapeutic target for solid tumors. In search of novel small molecule HIF-1 inhibitors, 5400 natural product-rich extracts from plants, marine organisms, and microbes were examined for HIF-1 inhibitory activities using a cell-based reporter assay. Bioassay-guided fractionation and isolation, followed by structure elucidation, yielded three potent natural product-derived HIF-1 inhibitors and two structurally related inactive compounds. In a T47D cell-based reporter assay, manassantin B1, manassantin A, and 4-O-methylsaucerneol inhibited hypoxia-induced HIF-1 activation with IC50 values of 3, 3, and 20 nM, respectively. All three compounds are relatively hypoxia-specific inhibitors of HIF-1 activation, in comparison to other stimuli. The hypoxic induction of HIF-1 target genes CDKN1A, VEGF, and GLUT-1 were also inhibited. These compounds inhibit HIF-1 by blocking hypoxia-induced nuclear HIF-1alpha protein accumulation without affecting HIF-1alpha mRNA levels. In addition, preliminary structure-activity studies suggest specific structural requirements for this class of HIF-1 inhibitors.
Hossain
Chowdhury Faiz
CF
Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
Kim
Yong-Pil
YP
Baerson
Scott R
SR
Zhang
Lei
L
Bruick
Richard K
RK
Mohammed
Kaleem A
KA
Agarwal
Ameeta K
AK
Nagle
Dale G
DG
Zhou
Yu-Dong
YD
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032134:Saururaceae / Q000737:chemistry*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017705:Lignans; D009687:Nuclear Proteins; D014157:Transcription Factors