TY - JOUR
T1 - Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis
AU - Hattori, Hisanori
AU - Okuda, Kensuke
AU - Murase, Tetsuji
AU - Shigetsura, Yuki
AU - Narise, Kosuke
AU - Semenza, Gregg L.
AU - Nagasawa, Hideko
N1 - Funding Information:
This work was supported in part by Kowa Life Science Foundation (K.O.), the Research Foundation for the Electrotechnology of Chubu (K.O.), Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research (B), 20790100 to H.N.), and Api Co., Ltd (H.N.). We thank Yamada Bee Farm for providing us with Brazilian green propolis. We also thank Mr. Tatsuya Watarai, Ms. Minae Noda, and Ms., Emi Inaba for their technical assistance.
PY - 2011/9/15
Y1 - 2011/9/15
N2 - 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/100 g 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.
AB - 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/100 g 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.
KW - Angiogenesis inhibitor
KW - Brazilian green propolis
KW - Drupanin
KW - HIF-1 modulator
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=80052601576&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052601576&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.07.060
DO - 10.1016/j.bmc.2011.07.060
M3 - Article
C2 - 21865046
AN - SCOPUS:80052601576
SN - 0968-0896
VL - 19
SP - 5392
EP - 5401
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 18
ER -