HPLC and HPLC-MS Analysis of Intestinal Elimination and Phase 2 Metabolism of 4'-hydroxy-4-Methoxychalcone and its Bis-Mannich Analog In The Rat (original) (raw)
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Toxicology, 2005
Cytochrome P4501A activity, oxidative stress and inhibition of gap junctional intercellular communication (GJIC) are involved in metabolic activation of promutagens and tumor-promoting activity of various xenobiotics, and their prevention is considered to be an important characteristic of chemoprotective compounds. In this study, a series of 31 chalcones and their corresponding dihydroderivatives, substituted in 2,2 -, 3,3 -, 4-or 4 -position by hydroxyl or methoxy group, were tested for their ability to inhibit Fe(II)/NADPH-enhanced lipid peroxidation and cytochrome P4501A-dependent 7-cethoxyresorufin-O-deethylase (EROD) activity in rat hepatic microsomes. Effects of the compounds on GJIC were determined in rat liver epithelial WB-F344 cells. Most of the chalcones and dihydrochalcones inhibited EROD activity in a dose-dependent manner at the range 0.25-25 M, which was comparable to model flavonoid inhibitors ␣-naphthoflavone and quercetin. The chalcones exhibited higher inhibition activity than the corresponding dihydroderivatives. Mono and dihydroxylated chalcones, and dihydrochalcones showed none or only a weak antioxidant activity; trihydroxyderivatives inhibited in vitro lipid peroxidation significantly only at 50 M concentration. Potential adverse effects, namely inhibition of GJIC and/or cytotoxicity were detected after treatment of WB-F344 cells with a number of chalcone and dihydrochalcone derivatives, suggesting that they should be excluded from additional screening as chemoprotective compounds. Chalcones and dihydrochalcones substituted at 4-and/or 4 -position, which elicited no inhibition of GJIC, were further tested for the potential enhancing effects on GJIC. The present data seem to suggest that 4-hydroxy, 2 ,4 -dihydroxy-3-methoxy, 2,4,4 -trihydroxy, and 2 ,4,4 -trihydroxychalcone, 2 ,4-dihydroxy and 2 -hydroxy-AbbreviationsH. Forejtníková et al. / Toxicology 208 (2005) [81][82][83][84][85][86][87][88][89][90][91][92][93] 3,4-dimethoxydihydrochalcone might be promising chemoprotective compounds against CYP1A activity, and partly also against oxidative damage without inducing adverse effects, such as GJIC inhibition. In general, determination of potencies of tested compounds to inhibit GJIC should be involved in any set of methods for the in vitro screening of chemoprotective characteristics of potential drugs, in order to reveal their potential adverse effects associated with tumor promotion.
Journal of the Brazilian Chemical Society, 2016
4'-Hydroxychalcones have been reported to possess several beneficial biological effects. Several lines of evidence accumulated to demonstrate increased biological activities of the Mannich base derivatives of the parent 4'-hydroxychalcones. Bioactivities of chalcones and related α,β-unsaturated ketones are frequently associated with their reactivity with cellular thiols, such as GSH. For comparison of GSH reactivity, two bis Mannich bases of two 4'-hydroxychalcones were synthesized and reacted with GSH under non-cellular conditions. Reversed-phase thin layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC) analysis showed formation of two polar products which structures were confirmed by RP-HPLC-ESI-MS (RP-HPLC-electrospray ionization mass spectrometry) as 1:1 chalcone-GSH adducts in each case. At pH values below 8.0, the two bis Mannich bases showed higher GSH reactivity than two 4'-hydroxychalcones. Influence of the nature of the amino groups, the ring-B substituents and pH of the medium on reactivity was also investigated. The findings could serve as useful structure-activity information for subsequent molecular modification of thiol-reactive 4'-hydroxychalcones.
Biochimie, 2013
In order to better understand the antioxidant behavior of a series of polyphenolic 2 0-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as Hbonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UVevis spectroscopic method indicate that a hydroxyl group in position 5 0 induces the highest antioxidant activity. Consequently, 2,2 0 ,5 0-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2 0 ,5 0-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa À /fa À) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2 0 ,5 0trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases.
Absorption and elimination of (14C) hesperidin methylchalcone in the rat
European Journal of Drug Metabolism and Pharmacokinetics, 1981
Hesperidin methylchalcone resorption and excretion were studied in rats, using 14C-labelling. The level of radioactivity in the blood showed a peak 1-2 hours after oral administration of the labelled compound, at a dose of 10 mg/kg body weight. The blood kinetics pattern suggested an entero-hepatic cycle, which was demonstrated by i.v. administration of the compound at the same dose. The blood profiles for both administration routes, demonstrated that the bioavailability of the active principle was good. Urinary excretion was lower than faecal excretion after oral ingestion, and both were comparable after administration via the i.v. route. Moreover, excretion mainly occurred within the first 24 hours following administration. When hesperidin methylchalcone was given in a therapeutic, pharmaceutical formulation, its bioavailability was greatly improved. (This was not due to the alcoholic ingredient in the formula).
Molecular cytotoxic mechanisms of anticancer hydroxychalcones
Chemico-biological …, 2004
Chalcones are being considered as anticancer agents as they are natural compounds that are particularly cytotoxic towards K562 leukemia or melanoma cells. In this study, we have investigated phloretin, isoliquiritigenin, and 10 other hydroxylated chalcones for their cytotoxic mechanisms towards isolated rat hepatocytes. All hydroxychalcones partly depleted hepatocyte GSH and oxidized GSH to GSSG. These chalcones also caused a collapse of mitochondrial membrane potential and increased oxygen uptake. Furthermore, glycolytic or citric acid cycle substrates prevented cytotoxicity and mitochondrial membrane potential collapse. The highest pK a chalcones were the most effective at collapsing the mitochondrial membrane potential which suggests that the cytotoxic activity of hydroxychalcones are likely because of their ability to uncouple mitochondria.
ASSESSING THE DRUG ABILITY OF CHALCONES USING IN-SILICO TOOLS
Chalcones are very well known natural as well as synthetic compounds associated with diverse set of pharmacological activities. They have the potential to be developed as lead compounds for the discovery of antioxidant, anti-inflammatory and anticancer agents. Naturally occurring and synthetic chalcone compounds have shown safety profiles in clinical trials. To study impact of substitutions on drug-likeliness and ADME profile of chalcones, twenty chalcones were selected from literature and molecular properties such as partition coefficient (Log P) , molecular weight, number of H-bond acceptors and donors, molecular polar surface area(TPSA) and number of rotatable bonds were calculated using molinspiration software available on the website: http://www.molinspiration.com/cgi-bin/properties.ADME profile has been obtained using pre ADMET free online tool (preADMET). Results clearly demonstrated that all chalcones have very good oral absorption and oral bioavailability. It is also observed that 4-acetamido substitution had decreased chalcones permeability in to CNS. In vitro plasma protein binding of 4-acetamido chalcones is less when compared to other chalcones. Compounds 1-20 showed % HIA ranging from 95.58 to 100% and all compounds showed optimum Caco-2 cell permeability (19.15-56.39 nm/sec). Seven out of twenty chalcones (1,2,4,6,7,10,20) displayed optimum MDCK cell permeability (25-500 nm/sec). 4-acetamido group introduction on chalcone had a great impact on the physicochemical and ADME profile of these molecules.
A Comprehensive Review of Aminochalcones
Molecules
Chalcones, members of the flavonoid family, display a plethora of interesting biological activities including but not limited to antioxidant, anticancer, antimicrobial, anti-inflammatory, and antiprotozoal activities. The literature cites the synthesis and activity of a range of natural, semisynthetic, and synthetic chalcones. The current review comprehensively covers the literature on amino-substituted chalcones and includes chalcones with amino-groups at various positions on the aromatic rings as well as those with amino-groups containing mono alkylation, dialkylation, alkenylation, acylation, and sulfonylation. The aminochalcones are categorized according to their structure, and the corresponding biological activities are discussed as well. Some compounds showed high potency against cancer cells, microbes, and malaria, whereas others did not. The purpose of this review is to serve as a one-stop location for information on the aminochalcones reported in the literature in recent ye...
Frontiers in Pharmacology, 2021
Chalcones are among the leading bioactive flavonoids with a therapeutic potential implicated to an array of bioactivities investigated by a series of preclinical and clinical studies. In this article, different scientific databases were searched to retrieve studies depicting the biological activities of chalcones and their derivatives. This review comprehensively describes preclinical studies on chalcones and their derivatives describing their immense significance as antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive, and neuroprotective agents. Besides, clinical trials revealed their use in the treatment of chronic venous insufficiency, skin conditions, and cancer. Bioavailability studies on chalcones and derivatives indicate possible hindrance and improvement in relation to its nutraceutical and pharmaceutical applications. Multifaceted and complex underlying mechanisms of chalcone actions demonstrated their ability to modulate a n...
Malaysian applied biology, 2021
Evaluation of toxicity induced in laboratory animals is paramount to the screening step in the assessment of the safety profile of all compounds. 3-(2,5-dimethoxyphenyl)-1-(5-methyl furan-2-yl) prop-2-en-1-one (DMPF-1); synthetic chalcone derivative has been investigated due to its pharmacological properties, including its antinociceptive and anti-inflammatory. However, the safety profile of this compound is yet to be determined. The present study seeks to highlight the toxicity effect of this compound using acute and subacute toxicity studies in the mice model. A single highest dose (1000 mg/kg) and repeated dose (0.1, 0.5, 1, 5 and 10 mg/kg) of DMPF-1 supplementation were executed. All toxicity study performed was supported by behavioural and body weight changes, haematological, serum biochemical analysis, macroscopic and microscopic analysis of the vital organs. The present result simplifies that DMPF-1 compound supplementation for four weeks is non-toxic as it caused no significant alteration in mice body weight and behaviour. Besides, no significant changes in haematological and biochemical parameters were observed. Further evaluation of its safety profile was confirmed by the normal architecture of the tissues organs obtained. Collectively, this report showed that DMPF-1 was safe to be consumed.
SLOVENIAN VETERINARY RESEARCH
The aim of this study was to investigate the antioxidant activity and inhibitory effect of 2,4,4'-trihydroxychalcone on digestive enzymes related to obesity, including sucrase, α-amylase, and lipase. The in vitro antioxidant activities of three concentrations of 2,4,4'-trihydroxychalcone (100, 300, and 500 µg/ml) were determined using 2,2-diphenyl-1-picrylhydrazyl radical scavenging, reducing power, and ferrous ion chelating assays. Moreover, in vitro inhibition of lipase, α-amylase, and sucrase enzyme activities by 2,4,4'-trihydroxychalcone was determined using a specific assay for each enzyme. 2,4,4'-Trihydroxychalcone has been shown to have antioxidant properties and inhibits sucrase, α-amylase and lipase activities. These findings suggest that 2,4,4′-trihydroxychalcone demonstrated an antioxidant activity and can effectively inhibit the key enzymes related to obesity.