Evaluating cycvalon activity under conditions of chronic endotoxicosis models in rats

Using the results of instrumental and numerical investigations of structure — activity relationships among derivatives and structural analogs of cinnamic acid, we predicted and then experimentally proved the protective action of the new bile-expelling drug cycvalon (a cyclohexanone derivative) in rats under the conditions of model endotoxicosis. The drug effectively prevented cytotoxic damage of liver and kidney tissues related to the vascular and fibroplastic mechanisms. At the same time, cycvalon is of low effectiveness with respect to the development of lung tissue damage, chronic pneumonia, and pneumofibrosis. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 9, pp. 9–11, September, 2007.     

Synthesis and In Vitro Antioxidant Activity of New 3-Substituted-2-Oxindole Derivatives

A series of new 1,3-dihydro-3-hydroxy-3-(2-phenyl-2-oxoethyl)-2H-indol-2-ones (1a-g) and 1,3-dihydro-3-(2-phenyl-2-oxoethylidene)-2H-indol-2-ones (2a-g) were synthesised by Knoevenagel condensation of substituted indole-2,3-diones (isatins) with various acetophenones. The synthesised compounds were characterised by their physical data, elemental, IR, ¹H NMR, ¹³C NMR and mass spectral analyses and their in vitro antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay. These compounds showed moderate to good antioxidant activities as compared with the standard, ascorbic acid. The antioxidant potential of 3-hydroxy-3-substituted oxindoles (1a-g) increased in a concentration-dependent manner from 10 to 500 μg/ml with 5-fluoro and 5-methyl analogues showing maximum activity. Of 3-aroyl methylene indol-2-ones (2a-g), majority of compounds with halogen substitution at position 5 of isatin ring exhibited good antioxidant activity within a concentration range of 5-100 μg/ml and the maximum activity was observed at 20 and 25 μg/ml concentrations. Thus, our study provides evidence that some newly synthesised isatin derivatives exhibit substantial antioxidant activity at low concentrations.     

Total synthesis and anti-leishmanial activity of some curcumin analogues

Curcumin (1) an important yellow dye isolated from Curcuma longa rhizomes, exhibits a variety of pharmacological effects such as anti-inflammatory, antioxidant and antiviral activity. Ten curcuminoids (2-11) were synthesized by the condensation of 2,4-pentanedione with differently substituted benzaldehydes, using the boron complex approach, which avoided Knoevenagel condensation at C-3 of the diketone. The curcuminoids were assayed in vitro against Leishmania amazonensis promastigotes using pentamidine isethionate (CAS 140-64-7) as the reference drug. Compound (5) 1,7-bis-(2-hydroxy-4-methoxyphenyl)-1,6-heptadiene-3,5-dione) was the most effective.     

Effects of naringin on hydrogen peroxide-induced cytotoxicity and apoptosis in P388 cells

Flavonoids are widely recognized as naturally occurring antioxidants. Naringin (NG) is one of the flavonoid components in citrus fruits such as grapefruit. Hydrogen peroxide (H2O2) causes cytotoxicity through oxidative stress and apoptosis. In this paper, we examined the effects of NG on H2O2-induced cytotoxicity and apoptosis in mouse leukemia P388 cells. Cytotoxicity was determined by mitochondrial activity (MTT assay). Apoptosis and DNA damage were analyzed by measuring chromatin condensation and Comet assay (alkaline single cell gel electrophoresis), respectively. H2O2-induced cytotoxicity was significantly attenuated by NG or the reduced form of glutathione (GSH), a typical intracellular antioxidant. NG suppressed chromatin condensation and DNA damage induced by H2O2. These results indicate that NG from natural products is a useful drug having antioxidant and anti-apoptopic properties.     

Synthesis and Biological Screening of 5-{[(4,6-Disubstituted pyrimidine-2-yl)thio]methyl}-N-phenyl-1,3,4-thiadiazol-2-amines

A number of substituted-α,β-unsaturated carbonyl compounds (1a-i) were prepared by Claisen-Schmidt condensation of substituted acetophenone with selected araldehydes, which on cycloaddition with thiourea furnished 4,6-disubstituted pyrimidine-2-thiols (2a-i). Reaction of (2a-i) with ethyl chloroacetate followed by condensation with hydrazine hydrate yielded 2-[(4,6-disubstituted pyrimidine-2-yl) thio] acetohydrazides (4a-c). Condensation of compounds (4a-c) with phenyl isothiocyanate gave 2-{[(4,6-disubstituted pyrimidine-2-yl) thio] acetyl}-N-phenylhydrazinecarbothioamides (5a-c) which on treatment with concentrated sulphuric acid afforded titled compounds 5-{(4,6-disubstituted pyrimidine-2-yl) thio] methyl}-N-phenyl-1,3,4-thiadiazole-2-amines (6a-c). These compounds have been characterized on the basis of elemental analysis, IR, (1)H NMR and MS. Compounds have been evaluated for their anticancer and antioxidant activities. Compounds 2b, 2c and 6b exhibited significant antitumor activity against human breast cancer MCF 7 cell line. However, moderate antioxidant activity was observed with compounds 2c, 2d, 2g and 6b.     

Concise synthesis of licochalcone C and its regioisomer, licochalcone H

Licochalone C (7a) is a retrochalcone isolated from Glycyrrhiza inflata, which shows potent antioxidant properties and inhibition of bacterial growth and cellular respiration. Biological studies have suggested that licochalcone C attenuates the lipopolysaccharide and interferon-gamma induced inflammatory response by decreasing the expression and activity of inducible nitric oxide synthase and modulating the antioxidant network activity of superoxide dismutase, catalase, and glutathione peroxidase activity. Licochalcone C also inhibits NADH-cytochrome C reductase in the membrane fraction of Micrococcus luteus. Since pharmacological activity studies of licochalcone C are ongoing and the yield of the compound is poor from natural product, we report a concise four step synthesis of licochalcone C (7a) and its regioisomer, tentatively called licochalcone H (7b), by employing acid-mediated Claisen-Schmidt condensation as a key step with 6 and 20 % overall yield, respectively.     

Synthesis and biological evaluation of Val–Val dipeptide–sulfonamide conjugates

Novel Val–Val dipeptide–benzenesulfonamide conjugates were reported in this study. These were achieved by a condensation reaction of p-substituted benzenesulfonamoyl alkanamides with 2-amino-4-methyl-N-substituted phenyl butanamide using classical peptide-coupling reagents. The compounds were characterized using Fourier transform infrared, ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, and electrospray ionization–high-resolution mass spectrometry spectroscopic techniques. As predicted from in silico studies, the Val–Val dipeptide–benzenesulfonamide conjugates exhibited antimalarial and antioxidant properties that were analogous to the standard drug. The synthesized compounds were evaluated for in vivo antimalarial activity against Plasmodium berghei. The hematological analysis was also conducted on the synthesized compounds. At 50 mg/kg body weight, compounds 8a , 8d , and 8g–i inhibited the multiplication of the parasite by 48–54% on Day 7 of posttreatment exposure, compared with the 67% reduction with artemisinin. All the synthesized dipeptides had a good antioxidant property, but it was less when compared with vitamin C. The dipeptides reported herein showed the ability to reduce oxidative stress arising from the malaria parasite.     

Synthesis and metal ion binding activity of methyl 12-amino-13-nitro-7-oxo dehydrodeisopropylabietate derivatives

Starting from dehydrobaietic acid with the analogous structure of carnosic acid, the intermediate methyl 12-bromo-13-nitro-7-oxo dehydrodeisopropylabietate was synthesized through methylation, bromination, carbonylation, and nitration. Subsequently, the coupling of methyl 12-bromo-13-nitro-7-oxo dehydrodeisopropylabietate with aliphatic or aromatic primary amine by Ullmann condensation reaction produced a series of methyl 12-imino-13-nitro-7-oxo dehydrodeisopropylabietate derivatives. In order to probe their antioxidant effects through metal ion chelation mechanism, the metal ion binding abilities on Cu²⁺ and Fe²⁺ of these compounds were studied using fluorescence quenching method. The results indicated that each compound showed obvious chelation activity with the binding constants (K _A) of the 10² L?mol^?1 order of magnitude, which implied its potential pharmacology application as antioxidant by the inhibition of Feton reaction through chelation with Cu²⁺ and Fe²⁺.     

木芙蓉叶抗氧化活性成分谱效关系研究

目的 比较木芙蓉叶不同极性部位的抗氧化活性,测定乙酸乙酯部位抗氧化活性并建立HPLC指纹图谱,研究谱效关系。方法 以DPPH法和ABTS法评价抗氧化活性,筛选木芙蓉叶抗氧化活性最佳部位,测定13批不同产地木芙蓉叶最佳部位的抗氧化活性,并建立HPLC指纹图谱,进行相似度分析、聚类热图分析以及主成分分析(principal component analysis,PCA),并通过偏最小二乘回归法(partial least squares regression,PLSR)分析其谱效关系。结果 木芙蓉叶不同极性部位抗氧化活性强弱依次为乙酸乙酯部位>正丁醇部位>水部位>石油醚部位。13批木芙蓉叶乙酸乙酯部位有17个共有峰,共指认出5个成分,峰4为秦皮素,峰6为芦丁,峰8为异槲皮苷,峰10为山奈酚-3-O-芸香糖苷和峰15为银椴苷,13批样品的相似度在0.912～0.995。聚类热图分析和PCA将13批木芙蓉叶样品聚为两类;PLSR分析表明,峰3、峰4(秦皮素)、峰6(芦丁)、峰10(山奈酚-3-O-芸香糖苷)和峰12回归系数与抗氧化活性呈正相关,且贡献度较大(VIP>1)...     

Chemical and biochemical properties of casein-sugar Maillard reaction products.

The Maillard reaction (MR) involves the condensation reaction between amino acids or proteins with reducing sugars, which occurs commonly in food processing and storage. The Maillard reaction of Glc-, Fru- and Rib-casein was generated at 55 degrees C, pH 7.0 for up to 28 days. The browning and fluorescence of Glc- and Fru-casein increased with increasing heating time. The temporal development of browning and fluorescence of Rib-casein was relatively faster than Glc- and Fru-casein, respectively. Glc-, Fru- and Rib-casein all exhibited antioxidant activity against Fenton reactant-induced hydroxyl free radicals, while only Rib-casein exhibited a weak DPPH free radical scavenging in addition to preventing Fenton reactant-induced oxidation. It was suggested that casein-sugar MRPs work more efficiently to quench hydrophilic than hydrophobic radicals. All three MRPs showed no toxicity to Caco-2 cell at both low and high concentrations. There was no correlation between the browning and/or fluorescence temporal patterns and biochemical activity of the different sugar-casein generated MRPs.     

Synthesis,biological evaluation and in silico molecular docking of novel 1-hydroxy-naphthyl substituted heterocycles

The versatile precursor 2-acetyl-4-allyl-1-hydroxy naphthalene was synthesized efficiently via Claisen rearrangement 2-acetyl-1-allyloxynaphthalene. The Claisen-Schmidt condensation of latter precursor afforded the corresponding chalcones which were exploited to synthesize a series of potential heterocycles such as pyrazoline, isoxazoline, benzocoumarin and benzoflavone. The synthesized products showed potent antioxidant and antimicrobial activities. Chalcone 3c, naphthyl pyrazoline 6b and hydroxycoumarin 13 exhibited the highest activity as antioxidants. Their binding mode showed specialized recognition of hydroxycoumarin 13 with the triad key amino acids at the active site of the oxidoreductase enzyme (PDB code 1DXO). 1-Hydroxynaphth-2-yl pyrazoline (6b) revealed the highest efficacy against both Gram positive and negative bacterial species. In silico molecular docking of pyrazoline 6b endorsed its proper binding at the active site of the 2EX6 enzyme which explains its potent antibacterial activity in comparison with standard ampicillin.     

The mechanism of indole acetic acid cytotoxicity

The cytotoxic effect of IAA (1 mM) was examined in rat neutrophils and lymphocytes by: loss of membrane integrity (necrosis), DNA fragmentation, chromatin condensation and mitochondrial transmembrane potential (apoptosis). The following conditions were studied: (1) rat neutrophils (high peroxidase activity; (2) rat lymphocytes in the absence and presence of horseradish peroxidase; and (3) rat lymphocytes co-cultivated with rat neutrophils. Incubation of neutrophils with IAA induced loss of membrane integrity, chromatin condensation and DNA fragmentation. The same was observed in lymphocytes incubated with HRP and IAA or co-cultivated with neutrophils in the presence of IAA. Neutrophils and lymphocytes incubated with IAA presented a more pronounced depolarization of mitochondrial transmembrane potential after 12 h treatment. Incubation for 24 h in the presence of IAA (1 mM) showed increase in the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase. The addition of exogenous antioxidant enzymes (SOD and CAT) prevented the loss of cell membrane integrity induced by IAA. Therefore, the process of cell death induced by IAA involves ROS production.     

Quercetin attenuates cadmium-induced oxidative damage and apoptosis in granulosa cells from chicken ovarian follicles

The attenuating effect of quercetin on cadmium-induced oxidative damage and apoptosis was investigated in cultured granulosa cells from chicken ovarian follicles. Results showed that exposure to 5 μM CdCl(2) induced a decrease in granulosa cell number and viability, caused chromatin condensation and DNA fragmentation. Moreover, cadmium treatment markedly increased malondialdehyde level and decreased glutathione peroxidase and superoxide dismutase activities. Furthermore, cadmium provoked higher BAX expression, inhibited expression of BCL2 and X-linked inhibitor of apoptosis protein (XIAP) and activated caspase-3. However, simultaneous supplementation with 1 μg/ml quercetin protected granulosa cells against cadmium-induced cytotoxicity through attenuating lipid peroxidation, renewing antioxidant enzymes activities and alleviating apoptosis by modulating XIAP, BAX and BCL2 expression, and inhibiting caspase-3 activity. Therefore, these results suggested that quercetin, as a widely distributed dietary antioxidant, contributes potentially to prevent cadmium-induced cytotoxicity in granulosa cells through attenuating lipid peroxidation, elevating intracellular antioxidant status and inhibiting apoptosis to ensure reproductive health.     

Antioxidant activity of minimally processed (in modified atmospheres), dehydrated and ready-to-eat vegetables

The antioxidant activity of vegetables subjected to minimal processing (in MAP, and intended for cooking or for use in salads), dehydrated condiments and ready-to-eat vegetables such as soups and purees, was assessed by reference to their ability to scavenge lipoperoxyl and hydroxyl radicals and Trolox-equivalent antioxidant capacity. In the case, the MAP vegetables the measurements were repeated during eight days of storage in a domestic refrigerator and after cooking (boiling, microwaving, pressure cooking, griddling, frying and baking). MAP vegetables had a good or very good antioxidant capacity, and showed no significant loss of antioxidant activity or scavenging capacity compared with fresh vegetables. The cooking treatments that keep the antioxidant activity of MAP vegetables are microwaving, sautéing and baking. The most aggressive method of cooking were steaming, boiling and frying. The dehydrated condiments (tablets) showed higher antioxidant activity than the ready-to-eat soup. The enrichment of stews and casseroles, with dehydrated vegetable tablets, and the consumption of soup or vegetable purees represent an increased antioxidant intake in our diet. Also “ready-to-eat” vegetable soups show antioxidant activity after they have been submitted to heat treatment to increase their shelf-life. They can be recommended as alternatives in our non-stop “life style”.     

苗药地瓜藤UPLC指纹图谱及抗氧化活性谱效关系研究

目的 建立苗药地瓜藤的UPLC指纹图谱,研究其与抗氧化活性的谱效关系,筛选抗氧化活性成分群。方法 采用UPLC建立地瓜藤指纹图谱,运用《中药指纹图谱相似度评价系统》（2012版）进行相似度评价并指认共有峰,运用SPSS 16.0、SIMCA 14.1软件进行聚类分析( Hierarchical cluster analysis,HCA) 和主成分分析( Principal component analysis,PCA);采用1,1-二苯基-2-三硝基苯肼（DPPH）自由基清除法、2,2’-联氮-二（3-乙基苯并噻唑啉-6-磺酸）二铵盐（ABTS）自由基清除法和总抗氧化能力测定法（FRAP）评价16批地瓜藤抗氧化活性;运用灰色关联度分析( Grey relational analysis,GRA）、双变量相关分析、偏最小二乘回归分析（Partial least squares regression,PLSR）3种分析方法研究谱效关系。结果 建立了16批地瓜藤的UPLC指纹图谱并标定13个共有峰,相似度为0.613~0.996,同时指认出峰9为芦丁、峰10为异槲皮素、峰12为水仙苷,HCA结果显示样品共聚为两类,与PCA结果一致;16批地瓜藤均有不同程度抗氧化活性。GRA结果显示13个共有峰与抗氧化活性之间的关联度>0.8,均具有高关联性,双变量相关性分析及PLSR分析结果表明峰5、峰9（芦丁）、峰10（异槲皮素）、峰11、峰12（水仙苷）的相关系数及回归系数与抗氧化活性呈正相关,且贡献度较大(VIP>1),为抗氧化活性的主要有效成分。结论 16批地瓜藤均具有较好的抗氧化活性,其发挥抗氧化作用是内部抗氧化成分群协同作用的结果,而共有峰5、9、10、11、12所对应的成分与其抗氧化活性密切相关,揭示了地瓜藤抗氧化活性的药效物质基础。     

Computational Modeling,Synthesis, and Antioxidant Potential of Novel Phenylcarbamoylbenzoic Acid Analogs in Combating Oxidative Stress

A new series of phenylcarbamoylbenzoic acid analogs were designed, synthesized, and evaluated for their in vitro antioxidant activity, aiming to find a lead for the treatment of oxidative stress. The target compounds were prepared by substituting the core phenylcarbamoylbenzoic acid moiety with certain functionalities via simple and efficient synthetic strategies. A molecular modeling study was performed to evaluate the recognition of target compounds at the 3MNG binding pocket. The docking data revealed that compounds 8c and 9a selectively bind to the crucial amino acid residues in the active site of 3MNG. The in vitro antioxidant activity was determined by ABTS antioxidant assay. Compounds 8c , 9a , and 9b showed high antioxidant activity and are thus promising as potent antioxidant leads.     

Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B.

Danshensu (3-(3,4-dihydroxyphenyl) lactic acid) and salvianolic acid B, two natural phenolic acids of caffeic acid derivatives isolated from Salvia miltiorrhiza root of the most widely used traditional Chinese medicine for the treatment of various cardiovascular diseases, have been reported to have potential protective effects from oxidative injury. To better understand their biological functions, the in vitro radical scavenging and antioxidant activities of danshensu and salvianolic acid B were evaluated along with vitamin C. Both danshensu and salvianolic acid B exhibited higher scavenging activities against free hydroxyl radicals (HO()), superoxide anion radicals (O(2)(-)), 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals and 2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radicals than vitamin C. In contrary, danshensu and salvianolic acid B showed weaker iron chelating and hydrogen peroxide (H(2)O(2)) scavenging activities than vitamin C. As expressed as vitamin C equivalent capacity (VCEAC), the relative VCEAC values (mg/100ml) were in the order of salvianolic acid B (18.59) > danshensu (12.89) > vitamin C (10.00) by ABTS radical assay. The protective efficiencies against hydrogen peroxide induced human vein vascular endothelial cell damage were correlated with their antioxidant activities. Analysis of structure-activity relationship of these two compounds showed that the condensation and conjugation of danshensu and caffeic acid appears important for antioxidant activity. These results indicated that danshensu and salvianolic acid B are efficient radical scavengers and antioxidants, and salvianolic acid B is superior to danshensu. Their radical scavenging and antioxidant properties might have potential applications in food and healthcare industry.     

白术挥发油GC-MS指纹图谱与抗氧化活性的谱效关系研究

目的 研究白术挥发油指纹图谱与抗氧化活性的谱效关系,筛选主要抗氧化活性成分。方法 采用GC-MS测定不同产地的15批白术饮片挥发油指纹图谱,通过清除1,1-二苯基-2-苦腈基（DPPH）和Fe³⁺还原/抗氧化能力法测定白术挥发油的抗氧化能力,运用偏最小二乘回归法进行数据分析,研究白术挥发油指纹图谱和抗氧化活性的相关性,并筛选活性色谱峰。结果 28个匹配指纹峰中,对挥发油清除DPPH自由基活性贡献度最大的前5个峰依次为：峰11 > 峰25 > 峰2 > 峰4 > 峰24;对挥发油还原Fe³⁺能力贡献度最大的前5个峰依次为：峰11 > 峰8 > 峰14 > 峰19 > 峰26。其中峰11的峰面积与挥发油清除DPPH自由基能力和还原Fe³⁺能力均呈正相关。通过与对照品比对确定峰11为苍术酮,并具有显著的抗氧化活性。结论 苍术酮不仅是白术挥发油的主要成分,还是主要的抗氧化活性物质。     

Biologically active substances studied by voltammetric and spectrophotometric techniques

Sulfur-containing biologically active substances (BAS) demonstrate pronounced antioxidant properties. Glutathione, cysteine, cystine, methionine, taurine, and lipoic acid occupy special positions among sulfur-containing antioxidant compounds. The antioxidant properties of these sulfur-containing BAS have been characterized and analyzed using voltammetric and spectrophotometric data. All studied BAS showed more or less pronounced antioxidant activity. Lipoic acid and glutathione exhibited the maximum antioxidant activity, which agrees with data published in the literature. Methionine showed the minimum antioxidant activity among the group of investigated BAS. The antioxidant activity was compared on the basis of the international criterion of antioxidant properties of sulfur-containing BAS, oxygen radical absorbance capacity (ORAC) with respect to a reference antioxidant (glutathione). A correlation was found between results of the voltammetric and spectrophotometric analyses.     

Synthesis of novel 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives with antioxidant activity

A series of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives (2a–k) bearing different amino acids were synthesized by base condensation reaction. 3-Chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one(2) was obtained by N-acylation of 5H-dibenz[b,f]azepine (1). All the synthesized compounds were evaluated for their potential over antioxidant activities against inhibition of lipid peroxidation by β-carotene and linoleic acid assay and inhibition of human low-density lipoprotein (LDL) oxidation assay. Typically, compound 2 showed weak antioxidant activity, whereas coupling of different amino acids enhances the antioxidant activities based on the presence of different functional groups. Among the derivatives, compound 2d showed significant antioxidant activities followed by 2h, 2i, 2j and 2k.