In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: identifying sinensetin as a novel antiangiogenesis agent.
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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ABSTRACT: Important bioactive molecules are molecules that are pharmacologically active derived from natural sources and through chemical synthesis. Over the years many of such molecules have been discovered through bioprospective endeavours. The discovery of taxol from the pacific yew tree bark that has the ability in stabilising cellular microtubules represents one of the hallmarks of success of such endeavours. In recent years, the discovery process has been aided by the rapid development of techniques and technologies in chemistry and biotechnology. The progress in advanced genetics and computational biology has also transformed the way hypotheses are formulated as well as the strategies for drug discovery. Of equal importance is the use of advanced drug delivery vehicles in enhancing the efficacy and bioavailability of bioactive molecules. The availability of suitable animal models for testing and validation is yet another major determinant in increasing the prospect for clinical trials of bioactive molecules. IeJSME 2013 7 (Suppl 1): S32-46International e-Journal of Science, Medicine & Education. 04/2013; 7(Suppl 1):32-46.