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PubMed1993

Flavone acetic acid--from laboratory to clinic and back.

Flavone acetic acid ester (NSC 293015, LM 985) emerged from a series of flavonoids from Lyonnaise Industrielle Pharmaceutique (Lipha) screened by the National Cancer Institute. LM 985 showed modest but sufficient activity in the P388 pre-screen to progress to secondary evaluation on the solid colon 38, where significant activity was seen. On the basis of this particular profile LM 985 was selected by the Cancer Research Campaign (CRC) UK for phase I clinical trial. It was not recommended for phase II trial because of drug associated hypotension and the fact that it appeared to act as a pro-drug for flavone acetic acid (NSC 347512, LM 975, FAA) which was shown to be responsible for the dramatic solid tumor activity in mice. This was manifested as dramatic hemorrhage necrosis and involves a complex mechanism of action. FAA proceeded to clinical trial but unfortunately no anti-tumor activity was seen. A large amount of effort has been channelled into identifying the mechanisms of action of FAA in mice and it is clear that activity relies on a number of factors. Subcutaneous tumors respond dramatically whereas ascites tumors and tumor deposits in other sites are usually less responsive. Establishment of a tumor blood vasculature system appears necessary for response and adequate drug concentrations within a therapeutic window are necessary. From the large body of information available at present the most likely explanation for discrepancies in activity between mouse and man seems to relate to differences in the ability of the immune system to respond to FAA, although variation in the composition of the vasculature cannot yet be ruled out. Analogs of this type of compound are worth pursuing but it is necessary to examine them in appropriate model systems in order to predict for possible clinical activity.

Animals↗
PubMed2005

Vasorelaxant and antioxidant activity of flavonols and flavones: structure-activity relationships.

We investigated the structure-activity relationships regarding vascular and antioxidant activity of a range of synthetic flavonols and flavones with 3 or fewer hydroxyl (OH) or methoxyl substitutions. The relaxant responses and ability of the flavones/flavonols to inhibit phenylephrine (PE)- and Ca-induced contraction was determined in rat isolated thoracic aorta. The ability of these compounds to reduce the level of superoxide and preserve endothelium-dependent relaxation in the presence of oxidative stress was also examined. Four compounds impaired contraction to PE or Ca, in the potency order 3'-hydroxyflavonol>3',4'-dihydroxyflavonol>7,4'-dihydroxyflavonol>3',4'-dihydroxyflavone. Flavonol, 3',4'-dimethoxyflavonol, and flavone were significantly less active. The flavonoids caused concentration-dependent reductions in superoxide produced by rat aorta in the presence of NADPH. The most active compounds, 3',4'-dihydroxyflavonol and 7,4'-dihydroxyflavonol, preserved endothelium-dependent relaxation in the presence of oxidative stress caused by pyrogallol or xanthine/xanthine oxidase. The results indicate that the catechol group is not critical for vascular relaxant or antioxidant activity, but rather, the important determinants for higher vascular and antioxidant activity of these compounds are the presence of a C3 OH group and the total number of OH substituents, respectively. These results have allowed the identification of the structural characteristics that promote vascular and antioxidant activity of flavonols, which may lead to the development of agents useful in treatment of cardiovascular disease.

Acetylcholine↗
PubMed1987

Flavone limitations to root nodulation and symbiotic nitrogen fixation in alfalfa.

Transcription of the nodABC genes in Rhizobium meliloti is required for root nodule formation in alfalfa (Medicago sativa L.) and occurs when specific compounds, such as the flavone luteolin, are supplied by the host plant. Results reported here indicate how luteolin in the root and rhizosphere can affect subsequent N(2) fixation and plant growth. Previous experiments with ;Hairy Peruvian 32' (HP32), an alfalfa population produced from ;Hairy Peruvian' (HP) by two generations of selection for increased N(2) fixation and growth, found that HP32 had more root nodules and fixed more N(2) than the parental HP population. In the present study, flavonoid extracts of HP32 seedling roots are shown to contain a 60% higher concentration of compounds that induce transcription of a nodABC-lacZ fusion in R. meliloti than comparable extracts of HP roots. Chromatographic data indicated that HP32 roots had a 77% higher concentration of luteolin than HP roots. Adding 10 micromolar luteolin to the rhizosphere of HP seedlings increased nodulation, N(2) fixation, total N, and total dry weight but had no effect on nitrate assimilation. These data show that normal levels of flavone nodulation signals in the rhizosphere of HP alfalfa can limit root nodulation, symbiotic N(2) fixation, and seedling growth and suggest that one mechanism for increasing N(2) fixation can be the genetic enhancement of specific biochemical signals which induce nodulation genes in Rhizobium.

Journal Article↗
PubMed1993

Analgesic activity of certain flavone derivatives: a structure-activity study.

1. Flavone, its methoxy derivatives and flavanone were synthesized by standard methods and were tested for analgesic activity in mice by employing acetic acid writhing and tail flick methods. 2. All the tested compounds except flavanone exhibited significant dose-dependent analgesic activity in both the assay models. Some of the compounds were found to involve opioid mechanisms in their analgesic effect. 3. A definite structure-activity relationship was observed in the analgesic activity of flavone derivatives as well as in their mechanism of action.

Analgesics↗
PubMed2004

Vascular and anti-oxidant actions of flavonols and flavones.

1. Flavonols and flavones are plant-derived polyphenolic compounds that are commonly consumed in the diet. Epidemiological studies indicating that high dietary intake of flavonols reduces the risk of mortality due to coronary heart disease have provoked interest in the mechanism of this cardioprotective effect. 2. We have investigated the structure-activity relationships of a range of flavonols and flavones with regard to their vascular relaxant and anti-oxidant activity. In rat isolated thoracic aorta, the synthetic flavonol 3',4'-dihydroxyflavonol (DiOHF) was found to be a significantly more potent vasorelaxant than the naturally occurring compounds chrysin, apigenin, luteolin, quercetin and fisetin. Similarly, DiOHF was significantly more potent than those compounds in the inhibition of calcium-induced contraction of the rat aorta. 3. 3',4'-Dihydroxyflavonol was also found to significantly inhibit superoxide radical generation in a cell-free system in the presence of xanthine/xanthine oxidase or by rat isolated aorta in the presence of NADPH. In the presence of oxidant stress generated by pyrogallol or xanthine/xanthine oxidase, endothelium-dependent relaxation of rat aortic rings was impaired. 3',4'-Dihydroxyflavonol was able to significantly improve endothelium-dependent relaxation in the presence of those oxygen radical generators. 4. In addition, DiOHF was found to significantly improve dilatation in the rat hindquarters vasculature after exposure to ischaemia and reperfusion. 3',4'-Dihydroxyflavonol was found to be equally effective whether applied before ischaemia or during ischaemia just before reperfusion. 5. In conclusion, DiOHF is an effective vasodilator and anti-oxidant that is able to prevent vascular reperfusion injury. We suggest that DiOHF may be useful as an adjunct to thrombolytic therapy in the management of reperfusion injury.

Animals↗
PubMed1982

In vivo activation of zoxazolamine metabolism by flavone.

The metabolism of zoxazolamine to 6-hydroxyzoxazolamine by liver microsomes from neonatal rats is stimulated severalfold by the in vitro addition of flavone, a naturally occurring compound found in several plant species. The intraperitoneal injection of flavone into neonatal rats causes an immediate several-fold stimulation in the rate of total body metabolism of simultaneously administered zoxazolamine. This is the first demonstration of stimulation of oxidative drug metabolism in vivo by a zenobiotic that is an activator of hepatic microsomal.

Animals↗
PubMed1998

Evidence that a New Antibiotic Flavone Glycoside Chemically Defends the Sea Grass Thalassia testudinum against Zoosporic Fungi.

Significantly fewer thraustochytrid protists (zoosporic fungi) were observed in association with healthy leaf tissue of the marine angiosperm Thalassia testudinum than in association with sterilized samples that were returned to the collection site for 48 h. In support of the hypothesis that sea grass secondary metabolites were responsible for these differences, extracts of healthy T. testudinum leaf tissues inhibited the growth of the co-occurring thraustochytrid Schizochytrium aggregatum and deterred the attachment of S. aggregatum motile zoospores to an extract-impregnated substrate. By using S. aggregatum for bioassay-guided chemical fractionation, a new flavone glycoside was isolated and structurally characterized as luteolin 7-O-beta-d-glucopyranosyl-2"-sulfate. Whole-leaf tissue concentrations of this metabolite (4 mg/ml of wet leaf tissue) inhibited S. aggregatum attachment, and a significantly lower concentration (270 mug/ml) reduced thraustochytrid growth by 50%, suggesting that natural concentrations are at least 15 times greater than that needed for significant microbiological effects. These results offer the first complete chemical characterization of a sea grass sulfated flavone glycoside and provide evidence that a secondary metabolite chemically defends T. testudinum against fouling microorganisms.

Journal Article↗
PubMed2003

The genetic basis of C-glycosyl flavone B-ring modification in maize (Zea mays L.) silks.

Resistance to corn earworm (CEW) (Helicoverpa zea Boddie) has been attributed to high concentrations of C-glycosyl flavones and chlorogenic acid in maize (Zea mays L.) silks. The most common C-glycosyl flavones isolated from maize silks are maysin, apimaysin, and methoxymaysin, which are distinguished by their B-ring substitutions. For a better understanding of the genetic mechanisms underlying the synthesis of these compounds, we conducted a quantitative trait locus (QTL) study with two populations: (Tx501 x NC7A)F2 and (Tx501 x Mp708)F2. For chlorogenic acid, maysin, and methoxymaysin concentration, the major QTL for both populations was located on chromosome 4 near umc1963. For apimaysin, the major QTL in both populations was located at the position of the pr1 locus on chromosome 5. The QTL alleles on chromosome 4 that increased the synthesis of methoxymaysin significantly decreased the synthesis of maysin and chlorogenic acid. This decrease in maysin concentration was four-fold greater than the increase in methoxymaysin. Our results indicate that the QTL on chromosome 4, responsible for the increase in methoxymaysin synthesis, alters the dynamics of both the phenylpropanoid and flavonoid pathways.

Alleles↗
PubMed1998

Anti-picornavirus activity of synthetic flavon-3-yl esters.

The in vitro antiviral activity against picornaviruses (rhinovirus serotype 1B and 14, and poliovirus type 2) of new synthetic 3-hydroxyflavones, 3-acetoxyflavones, and substituted cinnamic and benzoic acid flavon-3-yl esters was evaluated. The maximum non-toxic concentration of compounds was determined in a human cell line (HeLa) suitable for the replication of the three viruses. Their antiviral potency was measured by a plaque reduction assay. Generally, rhinoviruses exhibited a higher sensitivity to the new flavonoids than poliovirus. Flavones, with sterically small substituents in position 3, showed good activity against both rhinoviruses tested. However, the introduction of bulky substituents in the same position resulted in analogues with a higher toxicity and often with a lower efficacy.

Antiviral Agents↗
PubMed2001

Two new 2'-oxygenated flavones from Andrographis elongata.

Two new 2'-oxygenated flavones, 5,2',6'-trihydroxy-7-methoxyflavone (3) and skullcapflavone I 2'-O-beta-D-(4"-E-cinnamyl) glucopyranoside (5), together with three known flavones, 7-O-methylwogonin (1), skullcapflavone I (2) and skullcapflavone I 2'-O-beta-D-glucopyranoside (4) were isolated from the whole plant of Andrographis elongata, and the structures were elucidated by FAB-MS and one- and two-dimensional (1D- and 2D)-NMR spectral studies including 1H-1H correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC) and rotating frame Overhauser enhancement spectroscopy (ROESY) experiments, and chemical studies.

Acanthaceae↗
PubMed2003

Aurones: a subclass of flavones with promising biological potential.

Aurones [2-benzylidenebenzofuran-3(2H)-ones] are the secondary metabolites natural compounds belong to the flavonoids family, and structurally are the isomers of flavones, widely present in fruits and flowers where they play significant role in the pigmentation of the part of plant in which they occur. Literature survey clearly indicates that flavones, chalcones, flavonols and isoflavones have been studied largely for their therapeutical potential. Somehow, aurones still are less studied and it is only recently that these compounds have begun to be investigated. In this review, we report the recent advances made on the therapeutical potential of aurones in different biological areas. Their synthesis, structure-activity relationships, the importance of the substitution pattern will also be discussed. Finally, some aspects regarding the possible development of aurones will be highlighted briefly.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Effect of environmental conditions (pH, oxygenation and temperature) on the cytotoxicity of flavone acetic acid and its dimethylaminoethyl ester.

Bioflavonoids are known to inhibit enzymes in the glycolytic pathway and have been reported to decrease tumour blood flow. The antineoplastic capabilities of flavone acetic acid (FAA), dimethylaminoethyl-flavone-8-acetate (FAA ester) and quercitin (Q) as a function of pH, level of oxygenation and in conjunction with hyperthermia or SR-4233. In vitro, exposure of FSaIIC murine fibrosarcoma cells to various concentrations of FAA or FAA ester for 1 h demonstrated that both drugs were slightly more toxic toward hypoxic cells at 37 degrees C and pH 7.40 (but were somewhat less cytotoxic at pH 6.45 and 37 degrees C) than towards normally oxygenated cells. The cytotoxicity of FAA and FAA ester increased only minimally by concomitant treatment of cells at 42 degrees C or 43 degrees C. When temperatures of tumour-bearing mice anaesthetized with chloral hydrate and pentobarbital were measured both FAA (200 mg/kg) and Q (200 mg/kg) caused a more rapid drop in tumour versus core temperature, indicating a relative shutdown of tumour blood flow had been produced by these flavonoids. In Hoechst 33342 dye-defined subpopulations, both FAA and Q were only minimally cytotoxic in the subpopulation enriched in euoxic (bright) cells, producing surviving fractions of 0.70 and 0.29, respectively but were approximately 2-fold and 3-fold respectively more toxic towards the subpopulation enriched in hypoxic (dim) cells. When FAA preceded hyperthermia approximately a 3-4-fold increase in cell kill resulted from the combination in both subpopulations. Finally, when SR-4233, a selective hypoxic cell cytotoxic agent, was administered prior to FAA or Q and followed by hyperthermia the level of tumour cell killing increased so that the surviving fractions were 0.009 and 0.0055, respectively, in the dim cell subpopulation. These results indicate that FAA, FAA ester and Q may be most effectively used in a setting involving a combined modality regimen with a focus on the hypoxic tumour cell population.

Animals↗
PubMed1998

Synthesis of flavone-2'-carboxylic acid analogues as potential antitumor agents.

Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synthesized compounds was evaluated towards four tumoral cell lines, and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. Direct cytotoxic activity was very low for all derivatives. However, almost all compounds showed a remarkable increase of indirect cytotoxicity. In particular, compound 3i, which has an F atom in the 7 position of the flavone ring, was able to increase significantly the macrophage's lytic properties, and has been selected for further investigations.

Adjuvants, Immunologic↗
PubMedDate not supplied

Induction of apoptosis by flavones, flavonols (3-hydroxyflavones) and isoprenoid-substituted flavonoids in human oral tumor cell lines.

Various flavones, flavonols (3-hydroxyflavones) and isoprenoid-substituted flavones (flavonols) were investigated for their cytotoxic activity. Most of these compounds were more cytotoxic against human oral squamous cell carcinoma and salivary gland tumor cell lines than human gingival fibroblasts. The cytotoxic activity of flavonoids was generally higher than that of tannin-related compounds. Flavonoids induced apoptotic cell death characterized by DNA fragmentation (as identified by TUNEL method) and activation of caspase(s) (as identified by degradation products of cytokeratin 18 with M30 monoclonal antibody). ESR spectroscopy revealed that higher concentrations of flavonoids produced radicals under alkaline conditions. However, not all of them enhanced the radical intensity of sodium ascorbate, suggesting that the redox potential of flavonoids differs considerably from samples to samples. Catalase failed to eliminate the cytotoxic activity of flavonoids, reducing the possibility of the involvement of hydrogen peroxide for the cytotoxicity induction by them.

Apoptosis↗
PubMed1998

[Studies on flavones of Epimedium bevicorum Maxim].

OBJECTIVE: To systematically develop Epimedium spp. and control their quality. METHOD: Using polyamide and macroporous adsorbent resins AB-8. The compounds were identified on the basis of spectrometric data and physical and chemical test. RESULT: Four flavones were isolated from the herb. They were identified as wushanicariin, baohuoside VI, kaempferol-3,7-O-alpha-L-dirhamnoside and hexandraside E. CONCLUSION: These flavones were isolated from the herb and identified for the first time.

Drugs, Chinese Herbal↗
PubMed2002

Two flavones from Scutellaria baicalensis Georgi and their binding affinities to the benzodiazepine site of the GABAA receptor complex.

A new flavone 6,2'-dihydroxy-5,7,8,6'-tetramethoxyflavone (1) together with one known flavone 5,7,2'-trihydroxy-6,8-dimethoxyflavone (2) were isolated from the roots of Scutellaria baicalensis Georgi. Their structures were elucidated on the basis of spectral evidence and their affinities for the benzodiazepine (BDZ) site of the GABAA receptor complex were evaluated with a radioligand receptor binding assay.

Animals↗
PubMedDate not supplied

Mono- or di-fluorinated analogues of flavone-8-acetic acid: synthesis and in vitro biological activity.

BACKGROUND: Previously, the antitumour activity of some flavone-8-acetic acid (FAA) derivatives substituted with an acid function in position 2 of the benzene ring was evaluated. The most active compound resulted the one bearing a fluorine atom in position 7 of the flavone nucleus. In this paper, we evaluated new mono- or di-fluorinated FAA derivatives. MATERIALS AND METHODS: The cytotoxicity towards two human ovarian adenocarcinoma cell lines, the capability to stimulate human mononuclear cells and murine macrophages' lytic properties were evaluated by MTT. Moreover, the potentiation of lipopolysaccharide (LPS) activity was studied by ELISA analysis of TNF-alpha release. RESULTS: The analogues showed a direct cytotoxicity comparable to that of 5,6-dimethyl-xanthen-9-one-4-acetic acid (DMXAA), at present in clinical trials. None of the tested compounds was able to stimulate human mononuclear cells' lytic properties after either 4- or 24-h treatment, while after 4-h treatment, the derivative 5a was more able to stimulate murine macrophages with respect to DMXAA. Moreover, a significant increase of 5c and 5d activation was obtained with LPS association, reflected by TNF-alpha production as well. CONCLUSION: Like FAA, the new fluorinated derivatives 5a, 5c and 5d showed remarkable activity in murine cells, but this was not confirmed in human models.

Adenocarcinoma↗