title: Saururus cernuus lignans--potent small molecule inhibitors of hypoxia-inducible factor-1.
abstract: 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.
authors.affiliation: Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Chowdhury Faiz
authors.initials: CF
authors.lastname: Hossain
authors.forename: Yong-Pil
authors.initials: YP
authors.lastname: Kim
authors.forename: Scott R
authors.initials: SR
authors.lastname: Baerson
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Richard K
authors.initials: RK
authors.lastname: Bruick
authors.forename: Kaleem A
authors.initials: KA
authors.lastname: Mohammed
authors.forename: Ameeta K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
mesh_terms: 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*
chemical_list: 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