Identification of novel anti-cancer agents, applying in silico method for SENP1 protease inhibition

Determination of the phenolic composition of sherry and table white wines by liquid chromatography and their relation with antioxidant activity

Introduction: Sentrin-specific protease 1 (SENP1) is a protein whose main function is deSUMOylation. SENP1 inhibits apoptosis, and increases angiogenesis, estrogen and androgen receptor transcription and c-Jun transcription factor, proliferation, growth, cell migration, and invasion of cancer. The in vivo and in vitro studies also demonstrated which natural compounds, especially phytochemicals, minerals, and vitamins, prevent cancer. More than 3,000 plant species have been reported in modern medicine. Natural compounds have many anti-cancerous andanti-turmeric properties such as antioxidative, antiangiogenic, antiproliferative, and pro-apoptotic properties. Methods: In this study, we investigated the interaction of some natural compounds with SENP1 to inhibit its activity. We also screened the ZINC database including natural compounds. Molecular docking was performed, and toxicity of compounds was determined; then, molecular dynamics simulation (MDS) and essential dynamics (ED) were performed on natural compounds with higher free binding energies and minimal side effects. By searching in a large library, virtual screening of the ZINC database was performed using LibDock and CDOCKER, and the final top 20 compounds were allowed for docking against SENP1. According to the docking study, the top three leading molecules were selected and further analyzed by MDS and ED. Results: The results suggest that resveratrol (from the selected compounds) and ZINC33916875 (from the ZINC database) could be more promising SENP1 inhibitory ligands. Discussion: Because these compounds can inhibit SENP1 activity, then they can be novel candidates for cancer treatment. However, wet laboratory experiments are needed to validate their efficacy as SENP1 inhibitors.

The present work aims to assess the antibacterial potential of phenolic extracts, recovered from plants obtained on the North East of Portugal, and of their phenolic compounds (ellagic, caffeic, and gallic acids, quercetin, kaempferol, and rutin), against bacteria commonly found on skin infections. The disk diffusion and the susceptibility assays were used to identify the most active extracts and phenolic compounds. The effect of selected phenolic compounds on animal cells was assessed by determination of cellular metabolic activity. Gallic acid had a higher activity, against gram-positive (S. epidermidis and S. aureus) and gram-negative bacteria (K. pneumoniae) at lower concentrations, than the other compounds. The caffeic acid, also, showed good antibacterial activity against the 3 bacteria used. The gallic acid was effective against the 3 bacteria without causing harm to the animal cells. Gallic and caffeic acid showed a promising applicability as antibacterial agents for the treatment of infected wounds.

Aims: Sentrin-specific protease -2 (SENP2) is involved in deSUMOylation. Increased deSUMOylation in murine hearts by SENP2 upregulation resulted in cardiac dysfunction and congenital heart defects. Natural compounds via regulating cell proliferation and survival, induce cell cycle cessation, cell death, apoptosis, and producing reactive oxygen species and various enzyme systems cause disease prevention. Then, natural compounds can be suitable inhibitors and since SENP2 is a protein involved in heart disease, so our aim was inhibition of SENP2 by natural products for heart disease treatment. Material and methods: Molecular docking and molecular dynamics simulation of natural products i.e. Gallic acid (GA), Caffeic acid (CA), Thymoquinone (TQ), Betanin, Betanidin, Fisetin, and Ebselen were done to evaluate the SENP2 inhibitory effect of these natural products. The toxicity of compounds was also predicted. Results: The results showed that Betanin constituted a stable complex with SENP2 active site as it revealed low RMSD, high binding energy, and hydrogen bonds. Further, as compared to Ebselen, Betanin demonstrated low toxicity, formed a stable complex with SENP2 via four to seven hydrogen bonds, and constituted more stable MD plots. Therefore, depending upon the outcomes presented herein, Betanin significantly inhibited SENP2 and hence may be considered as a suitable natural compound for the treatment of heart failure. Further clinical trials must be conducted to validate its use as a potential SENP2 inhibitor.

Several diabetic complications are associated with forming advanced glycation end products (AGEs). Different chemical and natural compounds are able to prevent the development of these products. In this study, glycosylation was induced as a model by incubating bovine serum albumin (BSA) with glucose. Consequently, BSA was treated with glucose and different concentrations (1.25, 2.5, and 5 μM) of syringic acid, gallic acid, ellagic acid, ferulic acid, paracoumaric acid, and caffeic acid for 4 and 6 weeks. Biochemical experiments comprise measurements of fluorescent AGEs, protein carbonyl contents, total thiol, hemolysis tests, and also malondialdehyde (MDA) levels in RBC. These demonstrated the antiglycating mechanism of these phenolic acids. Most of the phenolic acids used in this study reduced MDA levels and protected thiol residues in protein structures. They also inhibited the formation of fluorescent AGEs and RBC lysis, except gallic acid. Moreover, ferulic acid, paracoumaric acid, and caffeic acid proteins significantly prevent carbonylation. Molecular docking and simulation studies showed that ellagic, caffeic, gallic, and syringic acids could interact with lysine and arginine residues in the active site of BSA and stabilize its structure to inhibit the formation of AGEs. Our results suggest that phenolic acid could be used as a potential phytochemical against protein glycation and related diabetic complications.

Sparkling wines were elaborated with the nontraditional varieties Villenave, Niagara, Manzoni, and Goethe, and monitored in relation to the changes in phenolic composition, browning index, and glutathione content during 18 months of biological aging (sur lies). Important changes in the phenolic profile, browning index, and glutathione content were observed in the sparkling wines during the over-lees aging period. The major phenolic compound in the sparkling wines was tyrosol, followed by caffeic, trans-caftaric, and gallic acids, catechin and epicatechin. The biological aging led to an increase in the individual phenolic compounds, especially caffeic, gallic, and ellagic acids, and an increase in the browning index was also observed during the aging period. Caffeic acid was significantly correlated with browning and aging period in all sparkling wines, which indicates that this compound can be useful as a quality marker to monitoring the biological aging profile of white sparkling wines. The results obtained indicate that the aging period (sur lie) had an important influence on the changes in the unique phenolic profile of the sparkling wines elaborated with nontraditional varieties. PRACTICAL APPLICATION: In sparkling wines production, the secondary fermentation occurring in the sealed bottle during the vinification contributes greatly to their quality and sensory complexity. The Vitis labrusca and hybrid grapes varieties represent most of the grapes cultivated in Brazil being employed in the elaboration of juices and wines. These varieties present a great oenological potential and have not been explored yet regarding to the production of white sparkling wines. The use of these nontraditional grape varieties cultivated in South Brazil may be a viable alternative in the production of white sparkling wines with biological aging potential and particular bioactive properties.

In the present study, the phenolic acid and flavonoid composition of eight different honeys (acacia, pineapple, gelam, longan, borneo, rubber tree, sourwood and tualang honeys) originating from different regions of Malaysia are reported. Solid phase extraction followed by high performance liquid chromatography (HPLC) was used for their identification and quantification. A total of thirteen different phenolic compounds consisting of seven flavonoids and six phenolic acids were investigated. Among these phenolic compounds, five phenolic acids (gallic, caffeic, coniferic, benzoic and trans-cinnamic acids) and five flavonoids (catechin, myricetin, naringenin, hesperetin and kaempferol) were detected in the investigated honeys. Longan and tualang honeys contained the highest number (n = 7 for each) of phenolic compounds, while only five phenolic compounds were detected in acacia, borneo and rubber tree honeys. Among the phenolic acids, benzoic acid was the most abundant (75%) followed by caffeic acid, catechin, myricetin, gallic acid and naringenin. The mean concentrations of caffeic, gallic and benzoic acids as well as catechin in the analyzed Malaysian honeys were 2.49, 0.81, 0.64 and 0.61 mg/kg, respectively. Overall, our results indicate that the investigated Malaysian honeys are a good source of different types of phenolic acids and flavonoids, which are important antioxidants. Practical Applications The study provides an overview on phenolic and flavonoid composition of several types of Malaysian honeys. The phenolic composition of some honeys from Malaysia is reported for the first time in this study. The data can be useful for future in vivo studies that involve evaluation of honey's medicinal properties and provide an insight into the type of honey in Malaysia that contains high antioxidant properties. In addition, the sample preparation technique (solid phase extraction) used in this study can provide a basis for the extraction of similar phenolic compounds in other types of honey.

국내산 낙엽성 참나무류인 신갈나무, 상수리나무, 떡갈나무, 졸참나무, 갈참나무 및 굴참나무 수피의 추출성분의 구조를 규명하고 수종 상호간 성분의 특성 및 연관성 등을 조사하였다. 그 결과 신갈나무에서 화합물 2(ellagic acid, 0.03 g), 4 ((+)-catechin, 4.59 g), 6 (taxifolin, 3.35 g) 및 7 (glucodistylin, 20.52 g)을 상수리 나무에서는 화합물 1 (gallic acid, 0.18 g), 4 ((+)-catechin, 8.52 g), 5 ((+)-gallocatechin, 0.09 g), 6 (taxifolin, 0.54 g) 및 7 (glucodistylin, 3.28 g)을 떡갈나무에서는 화합물 1 (gallic acid, 0.38 g), 2 (ellagic acid, 0.11 g) 4 ((+)-catechin, 2.01 g), 5 ((+)-gallocatechin, 0.12 g) 및 7 (glucodistylin, 0.39 g)을 갈참나무에서는 2 (ellagic acid, 1.51 g), 4 (+)-catechin, 21.91 g) 및 7 (glucodistylin, 3.91 g)을 졸참나무에서는 2 (ellagic acid, 0.84 g), 4 ((+)-catechin, 0.82 g), 6 (taxifolin, 4.02 g) 및 7 (glucodistylin, 21.50 g)을 굴참나무에서는 1 (gallic acid, 0.24 g), 3 (caffeic acid, 0.05 g), 4 ((+)-catechin, 0.32 g) 및 7 (glucodistylin, 0.65 g)을 분리하여 구조를 규명하였다. 국내산 참나무속 6 수종의 수피에서는 화합물 4 ((+)-catechin)와 7 (glucodistylin) 이 공통적으로 분리되었으며 두 성분 중 함유량이 상대적으로 높은 glucodistylin은 참나무류 수피의 지표성분 으로 이용될 수 있을 것이다. This study was carried out to investigate the chemotaxonomical correlation and chemical constituents of domestic Quercus spp. barks. The barks of Q. mongolica, Q. aliena, Q. serrata, Q. acutissima, Q. dentata, and Q. variabilis were collected in the experimental forest of Kangwon National University. The combined extracts were successively fractionated with n-hexane, methylene chloride and ethyl acetate using a separation funnel. A portion of the ethyl acetate and H2O soluble materials of each species were chromatographed on a Sephadex LH-20 column using various aqueous MeOH and EtOH-hexane as washing solvents. Spectrometric analysis such as NMR and MS, including TLC, were performed to characterize the structures of the isolated compounds. Ellagic acid (0.03 g), (+)-catechin (4.59 g), taxifolin (3.35 g), and glucodistylin (20.52 g) were isolated from Q. mongolica bark. Gallic acid (0.18 g), (+)-catechin (8.52 g), (+)-gallocatechin (0.09 g), taxifolin (0.54 g), and glucodistylin (3.28 g) were characterized from Q. acutissima bark. Gallic acid (0.38 g), ellagic acid (0.11 g), (+)-catechin (2.01 g), (+)-gallocatechin (0.12 g), and glucodistylin (0.39 g) were identified from Q. dentata bark. Ellagic acid (1.51 g), (+)-catechin (21.91 g), and glucodistylin (3.91 g) were purified from Q. aliena bark. Ellagic acid (0.84 g), (+)-catechin (0.82 g), taxifolin (4.02 g), and glucodistylin (21.50) were isolated from Q. serrata bark. Gallic acid (0.24 g), caffeic acid (0.05 g), (+)-catechin (0.32 g), and glucodistylin (0.65 g) were purified from Q. variabilis bark. (+)-Catechin and glucodistylin were isolated from all the barks. Glucodistylin can be a taxonomic index on Quercus spp.

Gordonibacter urolithinfaciens and Ellagibacter isourolithinifaciens are two human gut bacterial species that convert ellagic acid into urolithins. Urolithins are bioactive postbiotics produced by dehydroxylation reactions catalyzed by different catechol-dehydroxylases. The metabolic ability of these anaerobic bacteria on other dietary-phenolic compounds is unknown. In the present study, we evaluated the metabolism of flavonoids (quercetin, hesperetin, hesperidin, nobiletin, catechin, isoxanthohumol), isoflavonoids (daidzein), coumarins (esculetin, umbelliferone, scoparone), phenylpropanoids [caffeic acid; 3-(3',4'-dihydroxyphenyl)propanoic acid (dihydrocaffeic acid); rosmarinic acid, and chlorogenic acid], benzoic acid derivatives (gallic acid, ellagic acid), lignans (secoisolariciresinol diglucoside), stilbenes (resveratrol), and secoiridoids (oleuropein) by G. urolithinfaciens DSM 27213T and E. isourolithinifaciens DSM 104140T. Both strains metabolized ellagic acid leading to the characteristic urolithins. They also metabolized caffeic, dihydrocaffeic, rosmarinic, and chlorogenic acids. The rest of the phenolic compounds were not transformed. Catechol dehydroxylation and double bond reduction were prominent transformations observed during the incubations. The enzymatic activities seem to have a narrow substrate scope as many catechol- (quercetin, catechin, esculetin, gallic acid) and double bond-containing (resveratrol, esculetin, scoparone, umbelliferone) phenolics were not metabolized. The catechol-dehydroxylase activity was more efficient in E. isourolithinifaciens, while the reductase activity was more relevant in G. urolithinfaciens.

Background: Solanum dubium is a plant believed to have several therapeutic effects including anti-asthmatic properties. The objective of this study was to investigate the quantitative estimation of Gallic acid and Ellagic acid from the seed extract of Sudanese Solanum dubium. Methods: A simple and rapid high-performance thin-layer chromatographic method was developed and validated for quantitative estimation of Gallic acid and Ellagic acid from the seed extract of Sudanese Solanum dubium. Results: Ellagic acid and Gallic acid were quantified by using HPTLC. The seeds were found to contain 1.1% w/w of Ellagic acid and 2.1% w/w of Gallic acid in extract. Gallic acid and Ellagic acid were chromatographed on silica gel 60 F254 TLC plate using Toluene: Ethyl acetate – Methanol – Formic acid (3:3:1:0.4 v/v/v/v) as mobile phase and quantified by densitometric scanning at 280 nm. The method was found to give compact spots for Gallic acid (Rf 0.35) and Ellagic acid (Rf 0.21). The linear regression analysis data for standard Gallic and Ellagic acids spots showed good linear relationship with r2 = 0.988 and 0.994 respectively, in the concentration range 100-3000 ng/spot, accurate (99.23-102.7%), (98.7-100.2%); precise (% RSD ≤ 2); robust (% RSD ≤ 2) and specific. The LOD and LOQ of the method were found as 653 and 396.8ng/spot and 215.5and 130 ng/spot, of Gallic acid and Ellagic acid respectively. Conclusion: The method was validated for precision, recovery and repeatability as per the International Conference on Harmonization Guidelines for Gallic acid and Ellagic acid. Statistical analysis of the data showed that the method is precise, accurate, reproducible and selective for the analysis of Gallic acid and Ellagic acid.

Basilicum polystachyon (L.) Moench is a member of Lamiaceae family and important ethnomedicinal that is widely used in the treatment of several ailments and is reputed to possess an inhibitor of the dengue virus. In vitro propagation is an efficient strategy for large-scale production of plantlets. Such process is a good alternative method for the production of valuable secondary metabolites. Hence, the present study assesses the contents of phenolic compounds, radical scavenging activity and antimicrobial efficacy of in vivo grown compared with the in vitro grown B. polystachyon plants. Thus, the antioxidant capacity of leaf extracts was determined by scavengers like ABTS.+, DPPH., hydrogen peroxide, hydroxyl radical, nitric oxide along with lipid peroxidation inhibition, FRAP, reducing power and DNA damage protection assay. The antimicrobial activity was evaluated through disk diffusion assay and minimum inhibitory concentration assay. RP-HPLC was used to identify and quantify the phenolic compounds in the following forms: free, esterified and glycosylated. The leaf extract of in vivo plants exhibited stronger antioxidant activities. The FRAP assay revealed a maximum reducing power with leaf extract of in vivo grown plants (43.73±0.52 µM Fe(II) equivalent). Total phenolic content of in vivo plants presented a strong positive correlation to IC50 values of ABTS, DPPH, and HPSA, whereas total flavonoid content of in vitro grown plant was strongly correlated to IC50 values of DPPH and HPSA. In vivo plants showed the highest inhibition zone against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus. RP-HPLC analysis showed the phenolic compounds present in all tested forms of B. polystachyon leaf. For the first time, gallic acid, trans-cinnamic acid, ellagic acid, quercetin and vanillic acid were identified in this extract. Also, caffeic acid, p-coumaric acid and rosmarinic acid were quantified. These findings strongly suggest that B. polystachyon may be exploited as a promising natural source of antioxidants along with efficient antimicrobial agents.

Total polyphenols content (TPC), including flavonoids (rutin, mangiferin and kaempferol) and phenolic acids (gallic, caffeic and ellagic acid) from Physalis angulata were recovered by Ultrasound-Assisted Extraction and quantified by UV–vis and HPLC analysis. Process parameters were assessed through a Central Composite Rotatable Design (CCRD) and a model with regression coefficient equal to 0.9640, was used to establish the optimum conditions together with its respective response surfaces. The increase of ethanol percentage and solid-liquid ratio promoted a decrease on TPC but, on the other hand, the increase in the temperature led to an increase in the extraction of these compounds. Experimental results indicated a maximum amount of total polyphenols of 1.039 mg Gallic Acid Eqivalent (GAE) g-1 of extract, 104.88, 4.04, 8.37, 58.28, 13.26 and 1.87mg.L-1 for gallic acid, caffeic acid, ellagic acid, rutin, mangiferin and kaempferol, respectively.

The chemical composition of wine depends on the degree of maturity and quality of the grapes, as well as the agroecological conditions under which the grapes are grown. Tannins are of particular importance for wines, they are the source of the characteristic astringency of red wines. The main aim of this study was to investigate the influence of addition of enological tannins (0.05 g/L; 0.15 g/L; 0.3 g/L) on the phenolic composition of wine. The effect of the addition of differenttannins on the certain phenolic compounds (gallic acid, caffeic acid, ellagic acid and quercetin) was measured by HPLC analysis.Only forcontent of gallic and caffeic acid, there was a statistically significant difference between the control sample and all other samples with added tannins.

The biosynthetic pathway for gallic and ellagic acids in young, mature and autumn leaves ofAcer buergerianum andRhus succedanea was examined by tracer experiments, and also by isotope competition, withd-shikimic acid-14C,l-phenylalanine-U-14C,l-phenyllactic acid-U-14C, gallic acid-G-14C and their unlabeled compounds. In young leaves of both plants, the incorporation rate of labeled shikimic acid into gallic acid was significantly higher than that of labeled phenylalanine, whereas in the mature and autumn leaves the latter was a good precursor rather than the former for the gallic acid biosynthesis. Therefore, two pathways for gallic acid formation, through β-oxidation of phenylpropanoid and through dehydrogenation of shikimic acid, could be operating inAcer andRhus leaves, and the preferential pathway is altered by leaf age. In both plants, the incorporation rate of labeled phenyllactic acid during a 24 hr metabolic period was almost the same as that of labeled phenylalanine. The incorporation ofd-skikimic acid-G-14C,l-phenylalanine-U-14C andl-phenyllactic acid-U-14C into ellagic acid was very similar to the case of the radioactive gallic acid formation. Furthermore, regardless of the presence of unlabeled shikimic acid and/or phenylalanine, incorporation of the radioactivity of labeled gallic acid into ellagic acid occurred at a very high rate, suggesting the reciprocal radical reaction of gallic acid for the ellagic acid formation. The incorporation of labeled compounds into ellagitanins was also examined and their biosynthesis discussed further.

Guava (Psidium guajava L.) is a well known source of ascorbic acid, phenolic compounds and organic acids. Both ascorbic acid and phenolic components are powerful antioxidants and organic acids impart flavour in fruits. Gallic acid, chlorogenic acid, catechin, epicatechin, caffeic acid, ellagic acid and p-coumaric acid as phenolic components and ascorbic acid, oxalic acid, citric acid, tartaric acid and malic acid as organic acids were identified in fruits of six guava varieties at edible ripe stage using HPLC-PDA. Maximum amount of ascorbic acid (234.80 mg 100g-1) was recorded in Dhawal followed by Allahabad Safeda (198.80 mg 100g-1). Among the phenolic compounds, gallic acid, chlorogenic acid and catechin were the predominant ones. Maximum amounts of gallic acid (8.00 mg 100g-1), chlorogenic acid (9.00 mg 100g-1) and epicatechin (6.00 mg 100g-1) were detected in Shweta. Lalit had maximum amounts of catechin, ellagic acid, caffeic acid and p-coumaric acid (6.00, 5.93, 2.46 and 0.90 mg 100g-1, respectively). Citric acid was the major organic acid noticed in guava fruits distantly followed by tartaric acid. Lalima contained maximum amounts of citric acid (460.00 mg 100g-1) and malic acid (2.50 mg 100g-1). The genotype Sardar possessed maximum amount of tartaric acid (71.00 mg 100g-1) and Dhawal that of oxalic acid (18.50 mg 100g-1). In terms of ascorbic acid, Dhawal and Allahabad safeda were the best varieties for consumption, while Shweta and Lalit were the best varieties to consume having anticancer antioxidant phenolic components.