title: Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis.
abstract: The tumor microenvironment is characterized by hypoxia, low-nutrient levels, and acidosis. A natural product chemistry-based approach was used to discover small molecules that modulate adaptive responses to a hypoxic microenvironment through the hypoxia-inducible factor (HIF)-1 signaling pathways. Five compounds, such as baccharin (3), beturetol (4), kaempferide (5), isosakuranetin (6), and drupanin (9), that modulate HIF-1-dependent luciferase activity were identified from Brazilian green propolis using reporter assay. Compounds 3, 9 and 5 reduced HIF-1-dependent luciferase activity. The cinnamic acid derivatives 3 and 9 significantly inhibited expression of the HIF-1α protein and HIF-1 downstream target genes such as glucose transporter 1, hexokinase 2, and vascular endothelial growth factor A. They also exhibited significant anti-angiogenic effects in the chick chorioallantoic membrane (CAM) assay at doses of 300 ng/CAM. On the other hand, flavonoids 4 and 6 induced HIF-1-dependent luciferase activity and expression of HIF-1 target genes under hypoxia. The contents (g/100g extract) of the HIF-1-modulating compounds in whole propolis ethanol extracts were also determined based on liquid chromatography-electrospray ionization mass spectrometry as 1.6 (3), 14.2 (4), 4.0 (5), 0.7 (6), and 0.7 (9), respectively. These small molecules screened from Brazilian green propolis may be useful as lead compounds for the development of novel therapies against ischemic cardiovascular disease and cancer based on their ability to induce or inhibit HIF-1 activity, respectively.
authors.affiliation: Laboratory of Medicinal & Pharmaceutical Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Hattori
authors.forename: Kensuke
authors.initials: K
authors.lastname: Okuda
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Murase
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shigetsura
authors.forename: Kosuke
authors.initials: K
authors.lastname: Narise
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001938:Brazil; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008968:Molecular Conformation; D011429:Propolis / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D051793:Hypoxia-Inducible Factor 1; D011429:Propolis