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In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: Identifying sinensetin as a novel antiangiogenesis agent
Author(s) -
Lam In Kei,
Alex Deepa,
Wang YouHua,
Liu Ping,
Liu AiLin,
Du GuanHua,
Yuen Lee Simon Ming
Publication year - 2012
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201100680
Subject(s) - chemistry , hesperetin , naringin , hesperidin , nobiletin , in vivo , pharmacology , angiogenesis , flavonoid , biochemistry , antioxidant , biology , cancer research , medicine , chromatography , alternative medicine , microbiology and biotechnology , pathology
Scope 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. Methods and results Human umbilical vein endothelial cells ( HUVEC s) in vitro and zebrafish ( D anio 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 G 0/ G 1 phase in HUVEC culture and downregulating the m RNA expressions of angiogenesis genes flt1, kdrl, and hras in zebrafish. Conclusion The in vivo structure–activity relationship ( SAR ) analysis indicated that a flavonoid with a methoxylated group at the C 3′ position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C 8 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.