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PubMedDate not supplied

Inhibition of protein-tyrosine kinase activity by flavanoids and related compounds.

A series of 22 flavanoids and related compounds were tested for their ability to inhibit the activity of a protein-tyrosine kinase purified from bovine thymocytes (p40). Flavones or flavanols with hydroxyl groups at C-5 and C-7 or with three hydroxyl groups on the phenyl ring were potent inhibitors of p40. The replacement of hydroxyl groups with methoxyl groups led to a substantial loss of inhibitory activity. The presence of methoxyl or rhamnosyl substituents at C-3 also abolished inhibitory activity. Kinetic analyses indicated that the flavone apigenin [2] was a competitive inhibitor of p40 with respect to ATP. Flavanones and isoflavones were relatively inactive as protein-tyrosine kinase inhibitors. The isoflavone genistein [17], which has been reported as a potent inhibitor of both pp60(v=src) and the epidermal growth factor receptor, was not an inhibitor of p40.

Animals↗

PubMedDate not supplied

Cytotoxicities of some flavonoid analogues.

An array of 55 flavones having a variety of substituents was evaluated for cytotoxicity in five cancer cell cultures: A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Fifteen of the 55 flavone derivatives were significantly active against at least one of these cell cultures, and 4'-[(t-butyldi-methylsily)oxy]-7,8-dihydroxy-3',5'- dimethoxyflavone [40] was the most active of all. Structure-activity relationships of these compounds are discussed.

Antineoplastic Agents↗

PubMed1992

Inhibitory effects of flavonoids on Moloney murine leukemia virus reverse transcriptase activity.

Several flavonoids were tested for their effects on Moloney murine leukemia virus reverse transcriptase activity. Four groups of flavonoids, namely flavones, flavanones, flavonols, and flavanonols, were studied, and it was found that flavonols and flavanonols were very active in this regard while flavones and flavanones displayed very low activity. Among the flavonoids tested, fisetin, quercetin, myricetin, kaempferol, morin, (+/-)-taxifolin, (+)-catechin, and (-)-epicatechin were shown to be highly effective in inhibiting the reverse transcriptase activity. Structure-activity relationship analysis of these flavonoids revealed that the simultaneous presence of free hydroxyl groups at positions 3 and 4' enhanced the reverse transcriptase inhibitory activity. Replacement of the 3-hydroxyl group with a monosaccharide or of the 4'-hydroxyl group with a methyl group reduced inhibitory activity. The double bond at position 2 and 3 of the flavonoid's pyrone ring is not essential for inhibiting reverse transcriptase activity. The flavonoids studied demonstrated ability to inhibit the reverse transcriptase activity using either (rA)n(dT)12-18 or (rC)n(dG)12-18 as template-primers.

DNA Polymerase I↗

PubMed1992

Isolation of potential cancer chemopreventive agents from Eriodictyon californicum.

Activity-based fractionation of Eriodictyon californicum resulted in the isolation of 12 flavonoids that inhibit the metabolism of the carcinogen benzo[a]pyrene by hamster embryo cells in tissue culture. One was identified as a new flavanone, 3'-methyl-4'-isobutyryleriodictoyol [1], on the basis of spectroscopic analysis and alkaline hydrolysis. The seven other active flavanones were identified as eriodictyol [2], homoeriodictyol [3], 5,4'-dihydroxy-6,7-dimethoxyflavanone [4], pinocembrin [5], sakuranetin [6], 5,7,4'-trihydroxy-6,3'-dimethoxyflavanone [7], and naringenin 4'-methyl ether [8]. Four active flavones were also isolated: cirsimaritin [9], chrysoeriol [10], hispidulin [11], and chrysin [12]. The high inhibition of benzo[a]pyrene metabolism and the activation of benzo[a]pyrene to ultimate carcinogenic DNA-binding metabolites by cirsimaritin and chrysoeriol at a concentration of only 10 micrograms/ml indicates that these flavones warrant further investigation in vivo as potential chemopreventive agents.

Animals↗

PubMed1995

Synthesis and evaluation of 3',5'-di-tert-butyl-4'-hydroxyflavones as potential inhibitors of low density lipoprotein (LDL) oxidation.

The novel flavones 6-28, which display structural analogies with the two well-known lipid peroxidation inhibitors, probucol [1] and butylated hydroxytoluene [2], were synthesized and studied in vitro for their ability to inhibit the copper sulfate or endothelial cell-induced lipid peroxidation of human low-density lipoprotein (LDL). Most of the flavones were active in the range of 0.1-1 microM.

Antioxidants↗

PubMed1999

Activities of plant-derived phenols in a fibroblast cell culture model

Fourteen plant phenols of five structural groups (flavones, flavonols, flavan-3-ol, isoflavones, and phenylpropanoids) demonstrated concentration-dependent inhibitory or modulatory effects in a fibroblast cell culture model. The most potent inhibitory activity in this investigation was exhibited by apigenin (4), with flavone (1), chrysin (2), and genistein (9) being of somewhat lesser potency. These findings help to provide a better understanding of the action of these plant phenols in inflammatory/immune responses.

Journal Article↗

PubMed2000

Evaluation of the total peroxyl radical-scavenging capacity of flavonoids: structure-activity relationships.

The antioxidant activity of a series of flavonoids against peroxyl radicals generated from thermal homolysis of 2, 2'-azobis-amidinopropane was determined by the Total Oxyradical Scavenging Capacity (TOSC) assay. Seven flavonoids with hydroxy and/or methoxy substitution were analyzed and compared to the water-soluble vitamin E analogue Trolox. The most active compound was the flavonol quercetin, followed by its 3-glycoside derivative rutin; these were 7 and 5 times, respectively, better scavengers of peroxyl radical than Trolox. Among the flavones with both hydroxy and methoxy substitution, the most active against peroxyl radicals was the 5,6,4'-trihydroxy-7,8,3'-trimethoxyflavone (thymonin), with a TOSC value 1.5 times greater than that of Trolox. The activity of the remaining flavones was in the following relative order: 5, 4'-dihydroxy-6,7,8,3'-tetramethoxyflavone > 5-hydroxy-3,6,7,3', 4'-pentamethoxyflavone (artemetin) > 5,4'-dihydroxy-3,6, 7-trimethoxyflavone > 5,6,7,8,2',3',4',5'-octamethoxyflavone (agehoustin A). The data suggest a potential role for dietary intake of flavonoid-containing foods in lowering the risk of certain pathophysiologies that have been associated with free-radical-mediated events.

Flavonoids↗

PubMed2003

Solubility enhancement of a hydrophobic flavonoid, luteolin by the complexation with cyclosophoraoses isolated from Rhizobium meliloti.

A plant flavone, luteolin is a well-known inducer of nod genes in the Rhizobium meliloti. Its poor aqueous solubility was greatly enhanced by the complexation with a family of cyclosophoraoses synthesized in R.meliloti. Nuclear magnetic resonance (NMR) spectroscopic analysis showed that the chemical shifts of the aromatic ring moieties of the luteolin were changed greatly by the complexation with cyclosophoraoses. Fourier transform infrared (FTIR) spectroscopic analysis also showed a restricted vibrational pattern in carbonyl stretching region of the luteolin due to the complexation. This effective complex formation of cyclosophoraoses with a plant flavone, luteolin, suggests that rhizobial cyclosophoraoses play an important role as a solubility enhancer of the hydrophobic legume-derived flavonoids.

Flavonoids↗

PubMed1997

Production of tumour necrosis factor-alpha by cultured human peripheral blood leucocytes in response to the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (NSC 640488).

The investigative anti-tumour agent 5,6-dimethylxanthenonone-4-acetic acid (DMXAA, NSC 640488), developed in this laboratory as an improved analogue of flavone acetic acid (FAA, NSC 347512), is currently in clinical trial. The ability of DMXAA to up-regulate tumour necrosis factor (TNF) mRNA and protein synthesis in cultured human peripheral blood leucocytes (HPBLs) has been investigated and compared with that of flavone acetic acid (FAA) and of bacterial lipopolysaccharide (LPS). Human peripheral blood leucocytes were isolated from buffy coats obtained from a blood transfusion centre and also from blood samples from laboratory volunteers. At a concentration of 400 microg ml(-1) and an incubation time of 2 h, DMXAA up-regulated mRNA synthesis in six of eight individuals tested, as measured by Northern blotting. The degree of up-regulation varied in different individuals from one to nine times that of control levels. In contrast, FAA caused no induction above that of control levels and in some cases suppressed expression relative to controls, extending previous data that DMXAA but not FAA up-regulates TNF mRNA in the human HL-60 tumour cell line. At the same concentration but with longer incubation times (6-12 h), DMXAA induced increases in TNF protein in 11 of 15 samples of HPBLs from buffy coats and also in 11 of 15 samples of HPBLs from volunteers, as measured by cytotoxicity assays with L929 cells. FAA caused no increase in TNF protein, while LPS induced TNF to approximately 20-fold higher levels than did DMXAA. Considerable heterogeneity of response was observed with both sources of HPBLs, and there was little or no correlation between the extent of TNF induction by DMXAA and LPS in individual samples. In vitro analysis of the response of human peripheral blood leucocytes to DMXAA may be a useful test in clinical trials of agents such as DMXAA.

Antineoplastic Agents↗

PubMed2003

Flavonoid intake and breast cancer risk: a case--control study in Greece.

Flavonoids have been investigated for possible inverse associations with various chronic degenerative diseases, but there are no epidemiologic data concerning a possible association between several of the main flavonoid categories and breast cancer risk. We have applied recently published data on the flavonoid content of several foods and beverages on dietary information collected in the context of a large case-control study of 820 women with breast cancer and 1548 control women, conducted in Greece. We found a strong, statistically significant inverse association of flavone intake with breast cancer. The odds ratio for an increment equal to one standard deviation of daily flavone intake (i.e. 0.5 mg day(-1)) was 0.87, with 95% confidence interval 0.77-0.97. The association persisted after controlling for fruit and vegetable consumption, or for other flavonoid intake. This inverse association is compatible with and may explain the reported inverse association of breast cancer with consumption of vegetables, particularly leafy vegetables. After controlling for dietary confounding, there was no association of breast cancer risk with flavanones, flavan-3-ols, flavonols, anthocyanidins or isoflavones.

Breast Neoplasms↗

PubMed2005

Contrasting action of flavonoids on phototoxic effects induced in human skin fibroblasts by UVA alone or UVA plus cyamemazine, a phototoxic neuroleptic.

The potential protective effects of the flavanol catechin, the flavonol quercetin, the flavones, luteolin and rutin, and the isoflavones, genistein and daidzein, against the photo-oxidative stress induced by ultraviolet A radiation (UVA) and by phototoxic reactions resulting from the interaction of UVA with drugs and chemicals, has been assessed with cultured human skin fibroblasts. Lipid peroxidation and cell death have been chosen as model photobiological damage induced by UVA alone or photosensitized by cyamemazine (CMZ) and its photoproduct possessing phototoxic properties. Contrasting effects of flavonoids are observed. The flavanol, the flavonol and the flavones may protect against lipid peroxidation and cell death induced by 30 J cm(-2) of UVA alone or CMZ plus 10 J cm(-2) UVA. On the other hand, an amplification of the photodamage may be observed with isoflavones. A concentration-dependence study demonstrates that among the protective flavonoids, quercetin is the most efficient. The very effective protection brought by quercetin may result from its ability to scavenge reactive oxygen species produced by the photo-oxidative stress. However, the modification of membrane properties and the alteration of the lysosomal function by quercetin may not be neglected in these protective effects. The amplification of the photodamage by isoflavones is in sharp contrast with previous literature data demonstrating photoprotection by genistein. As a consequence, it may be concluded that an eventual antioxidant action of genistein may strongly depend on cells and photosensitizers. Furthermore such contrasting pro-versus anti-oxidant effects have to be taken into account when using flavonoid mixtures of plant extracts.

Antipsychotic Agents↗

PubMed2004

Comparative analysis of topoisomerase IB inhibition and DNA intercalation by flavonoids and similar compounds: structural determinates of activity.

Flavonoids and other polyphenolic compounds have been shown to inhibit human topoisomerase IB (topo I) through both inhibition of relaxation activity and through stabilization of the cleavable complex (poisoning). Some flavonoids have also been shown to intercalate DNA, and an association of topoisomerase inhibition with intercalation has been noted. We surveyed 34 polyphenolic compounds, primarily flavonoid glycones and aglycones, for their ability to inhibit topo I and to intercalate DNA using an in vitro gel electrophoresis method. We show that the most potent topo I poisons are the flavones and flavonols, and that these generally, but not always, are found to be DNA intercalators. There was no clear correlation, however, of topo-I-poisoning activity with the degree of DNA unwinding. Surprisingly, both DNA intercalation and topo I poisoning were shown to occur with some flavone glycones, including the C-glycosylflavone orientin. Inhibition of relaxation activity by flavonoids was found to be difficult to quantify and was most likely to be due to non-specific inhibition through flavonoid aggregation. As part of a structure-activity analysis, we also investigated the acid-base chemistry of flavonoids and determined that many flavonoids show acid-base activity with a pK(a) in the physiological pH region. For this reason, subtle pH changes can have significant effects on solution activity of flavonoids and their concomitant biological activity. In addition, these effects may be complicated by pH-dependent aggregation and oxidative degradation. Finally, we develop a simple model for the intercalation of flavonoids into DNA and discuss possible consequences of intercalation and topoisomerase inhibition on a number of cellular processes.

Animals↗

PubMed2003

Purification and properties of a new S-adenosyl-L-methionine:flavonoid 4'-O-methyltransferase from carnation (Dianthus caryophyllus L.).

A new enzyme, S-adenosyl-l-methionine:flavonoid 4'-O-methyltransferase (EC 2.1.1.-) (F 4'-OMT), has been purified 1 399-fold from the tissues of carnation (Dianthus caryophyllus L). The enzyme, with a molecular mass of 43-45 kDa and a pI of 4.15, specifically methylates the hydroxy substituent in 4'-position of the flavones, flavanones and isoflavones in the presence of S-adenosyl-l-methionine. A high affinity for the flavone kaempferol was observed (Km = 1.7 micro m; Vmax = 95.2 micro mol.min-1.mg-1), while other 4'-hydroxylated flavonoids proved likewise to be suitable substrates. Enzyme activity had no apparent Mg++ requirement but was inhibited by SH-group reagents. The optimum pH value for F 4'-OMT activity was found to be around neutrality. Kinetic analysis of the enzyme bi-substrate reaction indicates a Ping-Pong mechanism and excludes the formation of a ternary complex. The F 4'-OMT activity was increased, in both in vitro and in vivo carnation tissues, by the inoculation with Fusarium oxysporum f. sp. dianthi. The enzyme did not display activity towards hydroxycinnamic acid derivatives, some of which are involved, as methylated monolignols, in lignin biosynthesis; the role of this enzyme could be therefore mainly defensive, rather than structural, although its precise function still needs to be ascertained.

Chromatography, Gel↗

PubMed2003

Cytosol-mitochondria transfer of reducing equivalents by a lactate shuttle in heterotrophic Euglena.

To assess the expression and physiological role of the mitochondrial NAD(+)-independent lactate dehydrogenase (iLDH) in Euglena gracilis, cells were grown with different carbon sources, and the d- and l-iLDH activities and several key metabolic intermediates were examined. iLDH activity was significant throughout the growth period, increasing by three- to fourfold from latency to the stationary phase. Intracellular levels of D- and L-lactate were high (5-40 mm) from the start of the culture and increased (20-80 mm) when the stationary phase was entered. All external carbon sources were actively consumed, reaching a minimum upon entering the stationary phase, when degradation of paramylon started. The level of ATP was essentially unchanged under all experimental conditions. Oxalate, an inhibitor of iLDH, strongly inhibited oligomycin-sensitive respiration and growth, whereas rotenone, an inhibitor of respiratory complex I, only slightly affected these parameters in lactate-grown cells. Isolated mitochondria exhibited external NADH-supported respiration, which was sensitive to rotenone and flavone, and an inability to oxidize pyruvate. Addition of cytosol, NADH and pyruvate to mitochondria incubated with rotenone and flavone prompted significant O2 uptake, which was blocked by oxalate. The data suggested that iLDH expression in Euglena is independent of substrate availability and that iLDHs play a key role in the transfer of reducing equivalents from the cytosol to the respiratory chain (lactate shuttle).

Adenosine Triphosphate↗

PubMed2000

Terpenoids and flavonoids from Artemisia species.

A phytochemical reinvestigation of the aerial parts of Artemisia sieversiana gave a new guaianolide and two known flavones (chrysosplenetin and 5-hydroxy-3',4',6,7-tetramethoxyflavone). Antifungal fractions derived from the chloroform extract of A. annua afforded two cadinane derivatives (arteannuin B and artemisinin), oleanolic acid, beta-sitosterol, stigmasterol, and the four flavones artemetin, bonanzin, eupalitin and chrysosplenetin. Their structures were elucidated by spectral methods. All isolates from the two species were tested in vitro for antifungal activity. Arteannuin B, a main sesquiterpenoid in A. annua, showed antifungal activity against one human (Candida albicans, MIC: 100 micrograms/ml) and four plant pathogenic fungi (Gaeumannomyces graminis var. tritici, Rhizoctonia cerealis, Gerlachia nivalis and Verticillium dahliae, MICs: 150, 100, 150 and 100 micrograms/ml, respectively) whereas others showed no antifungal activity. The MIC value of ketoconazole to C. albicans was 1.0 microgram/ml, and those of triadimefon to G. graminis var. tritici and R. cerealis 150 and 100 micrograms/ml.

Antifungal Agents↗

PubMed2003

Constituents of sage (Salvia officinalis) with in vitro affinity to human brain benzodiazepine receptor.

Benzodiazepine receptor binding assay-guided fractionation of the methanol extract from sage leaves ( Salvia officinalis L.) revealed three flavones and two abietane diterpenes functioning as benzodiazepine receptor-active components. Structural elucidation of the isolated pure compounds was performed by UV, EI-MS, ESI(pos)-MS/MS, as well as 1H- and 13C-NMR techniques. The flavones apigenin, hispidulin and cirsimaritin competitively inhibited 3H-flumazenil binding to the benzodiazepine receptor with IC50 values of 30, 1.3 and 350 microM, respectively. In addition, the affinities of the newly discovered diterpene receptor ligands, i. e., 7-methoxyrosmanol and galdosol, were characterized. 7-Methoxyrosmanol exhibited an IC50 value of 7.2 microM and galdosol showed the strongest binding activity to the benzodiazepine receptor with an IC50 value of 0.8 microM.

Cerebral Cortex↗

PubMed2003

Effects of selected flavonoids and caffeic acid derivatives on hypoxanthine-xanthine oxidase-induced toxicity in cultivated human cells.

Tissue damage as a result of oxygen radical generation may be involved in the pathogenesis of different diseases, carcinogenesis, aging and cell death. The inhibition of the proliferation rate of the immortalised human cell line ECV 304 after oxidant damage by oxygen radicals generated in a hypoxanthine-xanthine oxidase system and the protection provided by some selected flavone and flavonol glycosides as well as by caffeic acid and its derivatives was determined. The cytotoxicity of the reactive oxygen species was differentially influenced by selected flavonoids and seems to be determined by the pattern of substitution and by their lipophilicity. Apigenin and quercetin demonstrated the strongest effect on the inhibition of hypoxanthine-xanthine oxidase-induced toxicity (50 % restitution of the cells at a concentration of 0.36 microM and 3.1 microM, respectively). The beneficial effect of the flavonol glycosides rutin and hyperoside was weak, whereas flavone glycosides such as diosmin showed a better effect of protection.

Caffeic Acids↗

PubMed1995

Antifungal principles of Baccharis pedunculata.

Four compounds including a flavone, an acetylenic lactone, a prenylated coumarin, and a 3-methyl ether flavone were isolated from the dichloromethane leaf extract of Baccharis pedunculata (Mill.) Cabr. (Asteraceae). The latter three compounds were identified to be responsible for the antifungal activity against some human pathogenic and phytopathogenic fungi. The most active compound, lachnophyllum lactone, an acetylenic lactone, showed a very high toxicity (LD50 2 micrograms/ml) against human keratinocytes.

Antifungal Agents↗