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.
- SourceAvailable from: Lim Chooi Ling[Show abstract] [Hide abstract]
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.
- [Show abstract] [Hide abstract]
ABSTRACT: SCOPE: The study aimed to investigate the regioselectivity of methylation of luteolin (3',4',5,7-tetrahydroxyflavone) in human in vitro and in vivo. METHODS AND RESULTS: Recombinant human catechol-O-methyltransferase (COMT) and human liver S9 were utilized to study the kinetics of meta (3')- and para (4')- methylation of luteolin, and urine samples from volunteers after giving a luteolin-containing formulation were collected to determine the ratio of para-/meta-production. The results showed luteolin favored a para-methylation, with a ratio of of para-/meta-production in CL(int) (1.43 in recombinant human COMT and 1.47 in human liver S9), which was contrary to the known substrates of COMT. However, the result of urine sample assay showed a preference of meta-methylation with a ratio of of para-/meta-production (0.460 ± 0.126). To elucidate the mechanism for different preference of methylation of luteolin in vitro and in vivo, metabolism stability of the meta- and para-methylated luteolin was evaluated in human liver microsomes and recombinant human CYP450s, which revealed that para-methylated luteolin was more easily demethylated by human CYP1A2 and CYP3A4/5 than meta-methylated luteolin. CONCLUSION: Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.Molecular Nutrition & Food Research 02/2013; · 4.31 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.PLoS ONE 01/2014; 9(7):e100416. · 3.73 Impact Factor