Flavonoids are phenolic compounds found in most plants.Since flavonoids are naturally present in fruits, vegetables, and tea, they are an integral part of the human diet.1) Ingested flavonoids are absorbed by the gastrointestinal tract and have been found in blood plasma.2) Flavonoids possess various biological and pharmacological properties, such as antioxidant activity, 3) anti-HIV-1 activity, 4) and anti-inflammatory activity. 5) They seem to protect against cancer onset, 6) vascular dementia, 7) and coronary heart disease-related deaths. 8)Flavonoids also modulate the activities of enzymes that metabolize drugs. 9) Flavonoids form the largest class of phytoestrogens known. The binding affinity of a flavonoid for the estrogen receptor primarily depends on the positions of Aand C-ring hydroxyl groups. 10) Recently, two interesting pharmacological properties of flavonoids have been reported. 1) The polymethoxyflavone, tangeretin, protects against the development of experimentally-induced Parkinson's disease in rats.11) 2) Other polymethoxyflavones inhibit the cellular excretion of certain drugs-a process mediated by P-glycoprotein.12,13) Cytochrome P450s can remove a flavonoid C-4Ј methyl and can add a hydroxyl at the C-3Ј position.14,15) To understand the diverse pharmacological effects of dietary flavonoids, their metabolic pathways must be known.A previous study of ours 16) showed that both rat and human cytochrome P450s convert flavanones to the corresponding 2,3-trans-flavanonols and flavones; whereas, only the human enzyme can convert the flavanone to isoflavone. We also recently reported a procedure for the specific deuteration of flavanones.17) With these deuterated flavanones as substrates, we determined that, most likely, the initial step in flavanone P450-catalyzed metabolism is abstraction of a hydrogen radical from the C-2 or -3 position of the flavanone skeleton.After rats received flavanone via a stomach tube, the most common urinary metabolites found were those with the C-4 ketone reduced and those with hydroxyls added at positions C-3 and C-6.18) Another P450 metabolic study found that aromatic hydroxylation products, flavones, unusual quinoltype oxidation products, chromone derivatives, and flavan-4-ol derivatives were produced when several different flavanones were substrates.19) Therefore, although all flavonoids have a common three-ring skeleton, it appears that ring substituents determine the metabolic fate of a specific substrate.If demethylated and hydroxylated flavonoid P450 metabolic products, amongst others, are to be unequivocally characterized, their physical properties must be compared with known standards. Previously, we reported a synthetic procedure for (Ϯ)-2,3-trans-flavanonols, which are hydroxylated at the C-3 position.20,21) Consequently, only those compounds could be unquestionably identified as P450 metabolic products during our previous study. 16) In order to identify other metabolic monohydroxyflavanones, we have now developed procedures to synthetically produce these co...
To clarify the metabolic pathways of flavanones in mammals, the metabolism of (+/-)-flavanone and (+/-)-4'-methoxyflavanone by rat liver microsomes and recombinant human P450s in which structural changes are readily identifiable were examined. The beta-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent formation of flavone plus (+/-)-2,3-trans-flavanonol and of 4'-methoxyflavone plus (+/-)-2,3-trans-4'-methoxyflavanonol, respectively, by rat liver microsomes was observed. The same metabolites were generated by recombinant human P450s in addition to the formation of isoflavone from (+/-)-flavanone. The kinetic isotope effects in these reactions were examined using deuterated (+/-)-flavanone and (+/-)-4'-methoxyflavanone. There was a strong isotope effect in the production of flavanonols, but the isotope effect in the production of flavones was small. The results indicated that the P450-mediated conversion of (+/-)-flavanone and of (+/-)-4'-methoxyflavanone to the corresponding metabolites proceeded via abstraction of a hydrogen radical from the C-2- or C-3-position of the flavanone skeleton. The antioxidant properties of flavanone and its metabolites were examined by measuring superoxide-scavenging activity in a xanthine-xanthine oxidase-cytochrome c system. (+/-)-2,3-trans-Flavanonol had higher activity than that of other flavonoids. Flavanones are metabolized by mammalian P450s, providing important information relevant to the metabolism and pharmacological action of dietary flavanones.
Flavonoids are polyphenolic compounds that are diverse in both chemical structure and chemical properties. Since flavonoids are naturally present in fruits, vegetables and tea, they are an integral part of the human diet.1) Ingested flavonoids are absorbed by the gastrointestinal tract and have been found in body fluids and tissues. It is generally accepted that dietary flavonoids have important biological effects, such as decreasing the risk of death from coronary heart disease. 2)Other known biological properties of flavonoids include: antioxidant activity, 3) antiallergic activity, 4) and modulation of monooxygenase activity. 5,6) Recently two interesting properties of flavonoids have been reported. 1) Apparently, certain flavonoids can pass the blood-brain barrier because they were found to accumulate in rat brains. 7) 2) Certain flavonoids inhibit the cellular excretion of some drugs-a process mediated by P-glycoprotein. 8,9) Dietary flavonoids are probably ingested at sufficient levels to have significant pharmaceutical effects. Therefore, to understand the diverse pharmacological properties of flavonoids, their metabolism must be understood.We have studied the metabolism of flavanones by cytochrome P450. This enzyme mediates the formation of flavones, flavanonols and isoflavones from the corresponding flavanones. We postulated that cytochrome P450 abstracts a hydrogen radical from the C-2 or 3 position of the flavanone skeleton.10) In plants, cytochrome P450 also participates in isoflavone biosynthesis. For example, Hakamatsuka et al. 11) reported that the formation of daidzein (isoflavone) from liquiritigenin (flavanone) was dependent on isoflavone synthase (cytochrome P450). It appears that a hydrogen radical abstraction from flavanones, as mediated by cytochrome P450, is a relatively general reaction in flavonoid metabolism and biosynthesis. To further clarify these reaction mechanisms, regio-selective deuterated flavanones would be useful tools.Rasku et al. 12,13) reported the synthesis of polydeuteriumlabeled, polyhydroxylated flavones, flavonols and isoflavonoids with D 3 PO 4 · BF 3 /D 2 O as the deuteration reagent. Because polydeuteration might cause significant and undesirable changes to the flavanones' cytochrome P450 binding properties and/or the cytochrome P450 catalytic activitiesin comparison to the non-deuterated flavanones-a regio-selective deuteration is needed. Therefore, we developed a new method for specific deuteration of the C-3 position of flavanones.Since D 3 PO 4 and AcOD are commercially available and easily handled, these reagents are useful deuterating reagents and have been used for the experiments reported here. The method results in high yields of flavanone dideuteration and requires only short reaction times. Our experiments also allow us to suggest a reaction mechanism for the cyclization and the deuteration of 2Ј-hydroxychalcones. Results and DiscussionAs shown in Chart 1, monodeuterated chalcone 2 was synthesized from 4Ј-methoxychalcone 1 using Silva's method 14) (...
A total synthesis of optically pure (+)‐catechin pentaacetate has been established using the (‐)‐chalcon epoxide (100% ee) derived from 3,4,2′,4′,6′‐pentakis(methoxymethoxy)chalcon as the starting material. The optical purity of the product is confirmed by 1H nmr analysis in the presence of a shift reagent.
Two biflavones isolated from Taxus cuspidata were identified with ginkgetin (1) and sciadopitysin (2) which belong to C3′‐C8 connected biflavones. The conformation of 2 in the solid state was determined by X‐ray analysis and the conformations of 1 and 2 in the liquid state were discussed using nmr techniques. Complete assignments of 1H and 13C nmr spectra about 1 were made on the basis of COSY, HMQC, HMBC and nOe experiments.
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