Article

In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: identifying sinensetin as a novel antiangiogenesis agent.

Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Taipa, Macao SAR, PR China.
Molecular Nutrition & Food Research (impact factor: 4.3). 06/2012; 56(6):945-56. DOI:10.1002/mnfr.201100680 pp.945-56
Source: PubMed

ABSTRACT Polymethoxylated flavonoids are present in citrus fruit in a range of chemical structures and abundance. These compounds have potential for anticarcinogenesis, antitumor, and cardiovascular protective activity, but the effect on angiogenesis has not been well studied.
Human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish (Danio rerio) in vivo models were used to screen and identify the antiangiogenesis activity of seven polymethoxylated flavonoids; namely, hesperetin, naringin, neohesperidin, nobiletin, scutellarein, scutellarein tetramethylether, and sinensetin. Five, excluding naringin and neohesperidin, showed different degrees of potency of antiangiogenesis activity. Sinensetin, which had the most potent antiangiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes flt1, kdrl, and hras in zebrafish.
The in vivo structure-activity relationship (SAR) analysis indicated that a flavonoid with a methoxylated group at the C3' position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity. This study provides new insight into how modification of the chemical structure of polymethoxylated flavonoids affects this newly identified antiangiogenesis activity.

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Keywords

angiogenesis
 
angiogenesis genes flt1
 
antiangiogenesis activity
 
cardiovascular protective activity
 
chemical structure
 
chemical structures
 
citrus fruit
 
Danio rerio
 
Human umbilical vein endothelial cells
 
identified antiangiogenesis activity
 
inducing cell cycle arrest
 
inhibited angiogenesis
 
lower lethal toxicity
 
methoxylated group
 
new insight
 
polymethoxylated flavonoids
 
potent antiangiogenesis activity
 
scutellarein tetramethylether
 
stronger antiangiogenesis activity
 
vivo structure-activity relationship