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.