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PubMed2005

Synthesis of chalcone analogues with increased antileishmanial activity.

Eighteen analogues of an active natural chalcone were synthesized using xanthoxyline and some derivatives, and these analogues were tested for selective activity against both promastigotes and intracellular amastigotes of Leishmania amazonensis in vitro. Three analogues (10, 12, and 19) containing nitro, fluorine or bromine groups, respectively, displayed increased selective activity against the parasites as compared with the natural chalcone. The nitrosylated chalcone 10 was also tested intralesionally in infected mice and was found to be as effective as Pentostan reference drug at a dose 100 times higher than that of the chalcone in controlling both the lesion growth and the parasite burden.

Acetophenones↗

PubMed2004

Geranyl chalcone derivatives with antifungal and radical scavenging properties from the leaves of Artocarpus nobilis.

Antifungal activity guided fractionation of the n-butanol extract from the methanol extract of the leaves of Artocarpus nobilis furnished 2',4',4-trihydroxy-3'-geranylchalcone (1), 2 ',4',4-trihydroxy-3'-[6-hydroxy-3,7-dimethyl-2(E),7-octadienyl]chalcone (2), 2',4',4-trihydroxy-3'-[2-hydroxy-7-methyl-3-methylene-6-octaenyl]chalcone (3), 2',3,4,4'-tetrahydroxy-3'-geranylchalcone (4), 2',3,4,4'-tetrahydroxy-3'-[6-hydroxy-3,7-dimethyl-2(E),7-octadienyl]chalcone (5). The chalcones 3 and 5 are new natural products whereas 1 and 2 are reported first time from the family Moraceae. All these compounds showed good fungicidal activity against Cladosporium cladosporioides and high radical scavenging activity towards the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical in TLC bio-autography method.

Antifungal Agents↗

PubMed2004

Chalcones as potent tyrosinase inhibitors: the effect of hydroxyl positions and numbers.

The inhibition of tyrosinase is one of the major strategies to treat hyperpigmentation. Various limitations are associated with many of these inhibitors, such as high cytotoxicity, poor skin penetration and low stability in formulations. In continuation of our previous study [J. Agric. Food Chem. 51 (2003) 1201], showing that isoliquiritigenin chalcone (ILC) is a potent tyrosinase inhibitor, the present study aims to characterize the chalcone family as new tyrosinase inhibitors, and demonstrate their potential whitening potency. Nine mono-, di-, tri- and tetrahydroxychalcones were tested as inhibitors of tyrosinase mono- and diphenolase activities, showing that the most important factor in their efficacy is the location of the hydroxyl groups on both aromatic rings, with a significant preference to a 4-substituted B ring, rather than a substituted A ring. Neither the number of hydroxyls nor the presence of a catechol moiety on ring B correlated with increasing tyrosinase inhibition potency. 4-Hydroxychalcone (4-HC), ILC and Butein inhibited tyrosinase and shortened the lag period of enzyme monophenolase activity from about 490 min (control) to 30 min (ILC). As pigmentation also results from auto-oxidation, the antioxidant activity of 4-HC, ILC and Butein, were tested. Results showed that chalcones are also potent antioxidants, with Butein the most potent. We may conclude that chalcones are potentially potent new depigmentation agents, with their double effect of reduction and antioxidant activity. A deeper understanding of the relation between their structures to their potency will contribute to designing the optimal agents.

Antioxidants↗

PubMed2001

Chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities.

Chalcones were tested for estimating anti-aromatase, anti-3beta-hydroxysteroid dehydrogenase delta5/delta4 isomerase (3beta-HSD) and anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities in human placental microsomes. In the present study, we have demonstrated for the first time that chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities: these enzymes being considered as important targets in the metabolic pathways of human mammary hormone-dependent cells. Our results showed that naringenin chalcone and 4-hydroxychalcone were the most effective aromatase and 17beta-hydroxysteroid dehydrogenase inhibitors with IC50 values of 2.6 and 16 microM respectively. In addition, inhibitory effects of some flavones and flavanones were compared to those of the corresponding chalcones. A structure-activity relationship was established and regions or/and substituents essential for these inhibitory activities were determined.

17-Hydroxysteroid Dehydrogenases↗

PubMed2001

Antimalarial alkoxylated and hydroxylated chalcones [corrected]: structure-activity relationship analysis.

Chalcones with 2',3',4'-trimethoxy, 2',4'-dimethoxy, 4'-methoxy, 4'-ethoxy, 2',4'-dihydroxy, and 4'-hydroxy groups on ring B were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. The other ring A was quinoline, pyridine, naphthalene, or phenyl rings with electron-donating or electron-withdrawing substituents of varying lipophilicities. Trimethoxy 6 and 27, dimethoxy 7, 8, 29, and methoxy 31 analogues had good in vitro activities (IC(50) < 5 microM). 3-Quinolinyl ring A derivatives were well represented among the active compounds. Hydroxylated chalcones were less active than the corresponding alkoxylated analogues. When evaluated in vivo, 8 and 208 were comparable to chloroquine in extending the lifespan of infected mice. Multivariate data analysis showed that in vitro activity was mainly determined by the properties of ring B. Quantitative structure-activity relationship models with satisfactory predictive ability were obtained for various B ring chalcones using projections to latent structures. A model with good predictability was proposed for 19 active chalcones. Size and hydrophobicity were identified as critical parameters.

Animals↗

PubMed1998

Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis.

A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes.

Animals↗

PubMed2001

Antifungal chalcones from Maclura tinctoria.

Five prenylated flavonoids, including one new natural product, were isolated from an ethanol extract of the leaves of Maclura tinctoria (L.) Gaud. The new compound has been characterized as 2',4',4,2''-tetrahydroxy-3'-[3''-methylbut-3''-enyl]chalcone (1). The known compounds were identified as 2',4',4-trihydroxy-3'-[3''-methylbut-3''-enyl]chalcone (isobavachalcone) (2), 4,2'-dihydroxy-2''-[1-hydroxy-1-methylethyl]-2'',3''-dihydrofurano[4'',5'':3',4']chalcone (bakuchalcone) (3), 4,4',5''-trihydroxy-6'',6''-dimethyldihydropyrano[2'',3'':5',6'']chalcone (bavachromanol) (4), and 5,7,3',4'-tetrahydroxy-6,8-diprenylisoflavone (6,8-diprenylorobol) (5). All the isolated compounds were evaluated against the AIDS-related opportunistic fungal pathogens, Candida albicans and Cryptococcus neoformans. Compound 2 was active against both yeasts.

Antifungal Agents↗

PubMed2001

Reaction mechanism of chalcone isomerase. pH dependence, diffusion control, and product binding differences.

Chalcone isomerase (CHI) catalyzes the intramolecular cyclization of bicyclic chalcones into tricyclic (S)-flavanones. The activity of CHI is essential for the biosynthesis of flavanone precursors of floral pigments and phenylpropanoid plant defense compounds. We have examined the spontaneous and CHI-catalyzed cyclization reactions of 4,2',4',6'-tetrahydroxychalcone, 4,2',4'-trihydroxychalcone, 2',4'-dihydroxychalcone, and 4,2'-dihydroxychalcone into the corresponding flavanones. The pH dependence of flavanone formation indicates that both the non-enzymatic and enzymatic reactions first require the bulk phase ionization of the substrate 2'-hydroxyl group and subsequently on the reactivity of the newly formed 2'-oxyanion during C-ring formation. Solvent viscosity experiments demonstrate that at pH 7.5 the CHI-catalyzed cyclization reactions of 4,2',4',6'-tetrahydroxychalcone, 4,2',4'-trihydroxychalcone, and 2',4'-dihydroxychalcone are approximately 90% diffusion-controlled, whereas cyclization of 4,2'-dihydroxychalcone is limited by a chemical step that likely reflects the higher pK(a) of the 2'-hydroxyl group. At pH 6.0, the reactions with 4,2',4',6'-tetrahydroxychalcone and 4,2',4'-trihydroxychalcone are approximately 50% diffusion-limited, whereas the reactions of both dihydroxychalcones are limited by chemical steps. Comparisons of the 2.1-2.3 A resolution crystal structures of CHI complexed with the products 7,4'-dihydroxyflavanone, 7-hydroxyflavanone, and 4'-hydroxyflavanone show that the 7-hydroxyflavanones all share a common binding mode, whereas 4'-hydroxyflavanone binds in an altered orientation at the active site. Our functional and structural studies support the proposal that CHI accelerates the stereochemically defined intramolecular cyclization of chalcones into biologically active (2S)-flavanones by selectively binding an ionized chalcone in a conformation conducive to ring closure in a diffusion-controlled reaction.

Chalcone↗

PubMed2005

Metabolism of the alpha,beta-unsaturated ketones, chalcone and trans-4-phenyl-3-buten-2-one, by rat liver microsomes and estrogenic activity of the metabolites.

When chalcone and trans-4-phenyl-3-buten-2-one (PBO) were incubated with liver microsomes of untreated rats in the presence of NADPH, 4-hydroxychalcone and trans-4-(4-hydroxyphenyl)-3-buten-2-one (4-OH-PBO), respectively, were formed as major metabolites. Two minor metabolites of chalcone, 4'-hydroxychalcone and 2-hydroxychalcone, were also observed. The oxidase activity affording 4-hydroxychalcone was inhibited by SKF 525-A, disulfiram, ketoconazole, and alpha-naphthoflavone. The oxidase activities leading to 4-hydroxychalcone and 4'-hydroxychalcone were enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats, respectively. The activity generating 2-hydroxychalcone was enhanced in liver microsomes of 3-methylcholanthrene- and dexamethasone-treated rats. The oxidation of PBO to 4-OH-PBO was inhibited by SKF 525-A, ketoconazole, disulfiram, and sulfaphenazole. This activity was enhanced in liver microsomes of 3-methylcholanthrene-, acetone- and phenobarbital-treated rats. 4-Hydroxylation, 4'-hydroxylation, and 2-hydroxylation of chalcone were catalyzed by rat recombinant cytochrome P450 1A1, 1A2, and 2C6; by 1A1 and 2C6; and by 1A1 and 3A1, respectively. PBO was oxidized by cytochrome P450 1A1, 1A2, 2C6, and 2E1. Chalcone and PBO were negative in an estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, 4-hydroxychalcone, 2-hydroxychalcone, 4'-hydroxychalcone, and 4-OH-PBO exhibited estrogenic activity.

Animals↗

PubMed2006

A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome.

Chalcones and their derivatives have been shown to have potent anticancer activity. However, the exact mechanisms of cytotoxic activity remain to be established. In this study, we have evaluated a series of boronic chalcones for their anticancer activity and mechanisms of action. Among the eight chalcone derivatives tested, 3,5-bis-(4-boronic acid-benzylidene)-1-methyl-piperidin-4-one (AM114) exhibited most potent growth inhibitory activity with IC50 values of 1.5 and 0.6 microM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay, respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin-like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and murine double minute 2 protein. It is noteworthy that AM114 as a single agent was preferentially toxic to cells with wild-type p53 expression, whereas combination of this compound with ionizing radiation (IR) significantly enhanced the cell-killing activity of IR in both wild-type p53 and p53-null cells. Together, these results indicate that the boronic chalcone derivative AM114 induces significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome and provide a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.

Antineoplastic Agents↗

PubMed2004

Structure-activity relationship studies on chalcone derivatives: potent inhibition of platelet aggregation.

In an effort to develop potent antiplatelet agents with anti-inflammatory action, a novel series of anti-inflammatory chalcones was screened to evaluate their antiplatelet effects. Structure-activity relationships and mode of action were investigated and characterized. The antiplatelet effects of the chalcones on washed rabbit platelets and human platelet-rich plasma were evaluated. Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the chalcone derivatives. Collagen-induced platelet aggregation was potently inhibited by all the chalcone derivatives at 300 microM, except for compound 4 at 100 microM. Compounds 6, 7 and 9 significantly inhibited the aggregation of washed rabbit platelets induced by platelet-activating factor at 300 microM. Of the compounds tested in human platelet-rich plasma, compounds 2, 8 and 9 showed significant inhibition of secondary aggregation induced by adrenaline. It is concluded that the antiplatelet effect of 2, 8 and 9 is mainly owing to an inhibitory effect on thromboxane formation. The inhibitory effect of 6, 7 and 9 on platelet aggregation induced by platelet-activating factor could be owing to a calcium antagonizing effect or inhibition of intracellular calcium mobilization.

Animals↗

PubMed2018

Carnation I locus contains two chalcone isomerase genes involved in orange flower coloration.

Carnations carrying a recessive I gene show accumulation of the yellow pigment chalcononaringenin 2'-glucoside (Ch2'G) in their flowers, whereas those with a dominant I gene do accumulation the red pigment, anthocyanin. Although this metabolic alternative at the I gene could explain yellow and red flower phenotypes, it does not explain the development of orange flower phenotypes which result from the simultaneous accumulation of both Ch2'G and anthocyanin. The carnation whole genome sequencing project recently revealed that two chalcone isomerase genes are present, one that is consistent with the I gene (Dca60979) and another (Dca60978) that had not been characterized. Here, we demonstrate that Dca60979 shows a high level of gene expression and strong enzyme activity in plants with a red flower phenotype; however, functional Dca60979 transcripts are not detected in plants with an orange flower phenotype because of a dTdic1 insertion event. Dca60978 was expressed at a low level and showed a low level of enzyme activity in plants, which could catalyze a part of chalcone to naringenin to advance anthocyanin synthesis but the other part remained to be catalyzed chalcone to Ch2'G by chalcone 2'-glucosyltransferase, resulting in accumulation of anthocyanin and Ch2'G simultaneously to give orange color.

I gene↗

PubMed1999

[Chalcones and their heterocyclic analogs as potential antifungal chemotherapeutic agents].

Chalcones and their heterocyclic analogues show various biological effects, e.g. anti-inflammatory, antitumour, antibacterial, antituberculous, antiviral, antiprotozoal, gastroprotective, and others. The present review discusses in greater detail the fungistatic and fungicide properties of these compounds and presents also their chemical structures. The mechanism of antifungal effects of chalcones and their analogues has not been investigated in greater detail. Due to the presence of a reactive ketovinyl moiety in the molecule the compounds of this type are able to react with the thiol groups of enzymes. It cannot be excluded that chalcones interfere with the normal function of the membranes of fungi and moulds. Further investigation of chemical, physical, and biological properties of chalcones and their analogues could lead to the elucidation of the mechanism of their action and finding of effective fungicidal and fungistatic agents in this group of organic substances.

Antifungal Agents↗

PubMed1977

Reactions of hydroxybenzofurans. VI. Syntheses of benzofuran chalcones, hydrazones and pyrazolines of potential biological activity.

Condensation of 5-acetyl-6-methoxy- (I) and 6-acetyl-5-methoxy-2,3-diphenylbenzofuran (II) with aromatic aldehydes gave the chalcones IIIa--f and IVa--f, respectively. Reaction of the chalcones IIIa--f and IVa--f with hydrazine hydrate-acetic acid mixture yielded the corresponding N-acetyl pyrazolines Va--f and VIa--f. The chalcones IIIa--f and IVa--f reacted with phenylhydrazine in ethanol to yield the corresponding phenylhydrazones VIIa--f and VIIIa--f. The latter hydrazones cyclize easily with boiling glacial acetic acid to the corresponding pyrazoline derivatives (IXa--f and Xa--f). The antibacterial activity of the chalcones and pyrazolines was investigated.

Bacteria↗

PubMed1996

Chalcone synthase in rice (Oryza sativa L.): detection of the CHS protein in seedlings and molecular mapping of the chs locus.

The chalcone synthase is a key enzyme that catalyses the first dedicated reaction of the flavonoid pathway in higher plants. The chs gene and its protein product in rice has been investigated. The presence of a chalcone synthase (CHS) protein in rice seedlings and its developmental stage-specific expression has been demonstrated by western analysis. The chalcone synthase of rice was found to be immunologically similar to that of maize. A rice cDNA clone, Os-chs cDNA, encoding chalcone synthase, isolated from a leaf cDNA library of an indica rice variety Purpleputtu has been mapped to the centromeric region of chromosome 11 of rice. It was mapped between RFLP markers RG2 and RG103. RG2 is the nearest RFLP marker located at a genetic distance of 3.3 cM. Some segments of chromosome 11 of rice including chs locus are conserved on chromosome 4 of maize. The markers, including chs locus on chromosome 11 of rice are located, though not in the same order, on chromosome 4 of maize. Genetic analysis of purple pigmentation in two rice lines, Abhaya and Shyamala, used in the present mapping studies, indicated the involvement of three genes, one of which has been identified as a dominant inhibitor of leaf pigmentation. The Os-chs cDNA shows extensive sequence homology, both for DNA and protein (deduced), to that of maize, barley and also to different monocots and dicots.

Acyltransferases↗

PubMed1984

Phytoalexin synthesis in soybean cells: elicitor induction of phenylalanine ammonia-lyase and chalcone synthase mRNAs and correlation with phytoalexin accumulation.

A glucan elicitor from cell walls of the fungus Phytophthora megasperma f. sp. glycinea, a pathogen of soybean (Glycine max), induced large and rapid increases in the activities of enzymes of general phenylpropanoid metabolism, phenylalanine ammonia-lyase, and of the flavonoid pathway, acetyl-CoA carboxylase and chalcone synthase, in suspension-cultured soybean cells. The changes in phenylalanine ammonia-lyase and chalcone synthase activities were correlated with corresponding changes in the mRNA activities encoding these enzymes, as determined by enzyme synthesis in vitro in a mRNA-dependent reticulocyte lysate. The time courses of the elicitor-induced changes in mRNA activities for both enzymes were very similar with respect to each other. Following the onset of induction, the two mRNA activities increased significantly at 3 h, reached highest levels at 5 to 7 h, and subsequently returned to low values at 10 h. Similar degrees of induction of mRNA activities and of the catalytic activities of phenylalanine ammonia-lyase and chalcone synthase were observed in response to three diverse microbial compounds, the glucan elicitor from P. megasperma, xanthan, an extracellular polysaccharide from Xanthomonas campestris, and endopolygalacturonase from Aspergillus niger. However, whereas the glucan elicitor induced the accumulation of large amounts of the phytoalexin, glyceollin, in soybean cells, endopolygalacturonase induced only low, albeit significant, amounts; xanthan did not enhance glyceollin accumulation under the conditions of this study. This result might imply that enzymes other than phenylalanine ammonia-lyase or chalcone synthase exert an important regulatory function in phytoalexin synthesis in soybean cells.

Acyltransferases↗

PubMed1985

Elicitor-induced phytoalexin synthesis in soybean cells: changes in the activity of chalcone synthase mRNA and the total population of translatable mRNA.

Rapid changes in the mRNA activity encoding chalcone synthase, a central enzyme involved in isoflavonoid phytoalexin synthesis, were induced in cultured cells of soybean (Glycine max) after treatment with a glucan elicitor from the cell walls of the fungus, Phytophthora megasperma f. sp. glycinea, a soybean pathogen. Two-dimensional gel electrophoresis of the in vitro- and in vivo-synthesized chalcone synthase showed that it consisted of a group of proteins of similar molecular weights of about 41,000, but with differing isoelectric points between pH 6.1 and pH 7.1. Total activity of chalcone synthase mRNA increased as early as 40 to 60 min after the onset of elicitor induction, and reached a peak at about 4 h. Treatment with the fungal elicitor caused major changes in the population of total translatable RNA as indicated by two-dimensional electrophoresis of the translation products. The mRNA activities for at least 16 proteins were increased and for at least 4 proteins were decreased. The elicitor-induced changes in the population of translatable mRNA occurred at a rate similar to that observed for chalcone synthase mRNA activity. Our results suggest that soybean cells respond to the glucan elicitor by major metabolic changes at the RNA level including the enhanced capacity for phytoalexin synthesis.

Acyltransferases↗

PubMed1986

Isolation and characterization of buckwheat (Fagopyrum esculentum M.) chalcone synthase and its polyclonal antibodies.

Chalcone synthase was isolated from illuminated buckwheat (Fagopyrum esculentum M.) hypocotyls and purified to electrophoretic homogeneity by sodium dodecyl sulfate-polyacrylamide gel electrophoresis using (NH)4SO4 fractionation, gel filtration on AcA 44, ion exchange chromatography on DEAE-Bio-Gel, and HPLC on hydroxylapatite. The properties of the enzyme were pH optimum, 8.0; Mr approximately 83,000 +/- 1000; Mr subunit, approximately 41,500 +/- 500; isoelectric point, pH 5.2; Km, 1 X 10(-6)M for malonyl-CoA, and 0.6 X 10(-6) M for p-coumaryl-CoA. Buckwheat chalcone synthase used p-coumaryl-CoA as substrate and also utilized caffeyl-CoA and ferulyl-CoA at 20 and 80%, respectively, of the rate of p-coumaryl-CoA in the chalcone synthase reaction. Antibodies against the buckwheat chalcone synthase were developed in a New Zealand white rabbit and characterized for specificity by enzyme-linked immunosorbent assay, Ouchterlony double immunodiffusion, and Western blotting.

Acyltransferases↗