Design,synthesis and bioactivity of catechin/epicatechin and 2-azetidinone derived chimeric molecules

A new class of chimeric molecules have been developed. These are based on polyphenols like catechin and epicatechin and monocyclic β-lactams. The two units are joined via a triazole linker using the ‘Click Chemistry’ conditions. The compounds showed good to weak antibacterial activity against Escherichia coli as well as moderate inhibition of RNase A.     

Phenolic amides from the leaves of Nicotiana tabacum and their anti-tobacco mosaic virus activities

Three new phenolic amides, tabamides A–C (1–3), together with three known phenolic amides (4–6), were isolated from the leaves of Nicotiana tabacum. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1–6 were also tested for their anti-tobacco mosaic virus (anti-TMV) activity. The results showed that compound 1 exhibited high anti-TMV activity with inhibition rate of 38.6%, which is higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 15.3–26.5%, respectively.     

Design,synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones

A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of regioisomers 6 and 7 were resolved by 2D ¹H–¹H COSY, ¹H–¹³C HSQC and ¹H–¹³C HMBC experiments. The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability. Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds. The keto and phenolic –OH are major factors that are prominently involved in interaction with COX-2 active site.     

Loranthin: A new polyhydroxylated flavanocoumarin from Plicosepalus acacia with significant free radical scavenging and antimicrobial activity

A new flavanocoumarin, loranthin (1) together with catechin (2), quercetin (3) rutin (4), gallic acid (5) and methyl gallate (6) were isolated from Plicosepalus acacia. Loranthin possesses the rare flavanocoumarin skeleton in which the flavan and coumarin moieties are linked via C-7/C-8 of both moieties. The flavan moiety in 1 was found to be catechin, while a 3,5,6,7-tetrahydroxycoumarin fragment represented the other moiety in 1. The structures of the isolated compounds were established based on different spectroscopic data including HRFABMS, 1D and 2D NMR (COSY, HSQC, and HMBC). The free radical scavenging activities of different extracts and pure compounds were determined using DPPH reagent and all the tested samples revealed significant activities with variable percent. Loranthin exhibited a 38.4% inhibition in the free radical scavenging assay. The antimicrobial activity of loranthin was evaluated against several pathogen and loranthin displayed significant effect against Staphylococcus aureus. Moreover, the inhibition activity of the compounds against several disease-relevant protein kinases were also evaluated and discussed.     

Lung cancer and matrix metalloproteinases inhibitors of polyphenols from Selaginella tamariscina with suppression activity of migration

Cancer metastasis has been a major impediment to effective cancer treatment and is the major cause of cancer-related death. Polyphenols compounds have been reported to possess anti-metastasis activity through their inhibitory activity of matrix metalloproteinases (MMPs). In this paper, twelve polyphenols compounds, including three novel phenols, named selaphenins A–C (1–3), two known selaginellin derivatives (4 and 5), together with seven known biflavonoids (6–12) were isolated from the plant of Selaginella tamariscina. Their structures were elucidated by extensive spectroscopic analyses. Notably, polyphenols compound 10 suppressed the migration of A549 cells by primary targeting MMP-9. The antitumor activity of compound 10 was possibly due to the induction of cell apoptosis through intrinsic apoptosis pathways, accompanied by increasing the expression of Bax and caspase-3 in a dose-dependent manner. This study provides evidence that polyphenols analogues from S. tamariscina as inhibitors of MMP-9 exhibited potential migration inhibition activities.     

Effects of apple (Malus?×?domestica Borkh.) phenolic compounds on proteins and cell wall-degrading enzymes of Venturia inaequalis

Cell wall-degrading enzymes of Venturia inaequalis are supposed to be fungal virulence factors whereas phenolic compounds of the host plant may be involved in defence. Since phenolic structures are predestined for an interaction with proteins we studied the effects on enzymes and proteins in course of in vitro culture and with preparations from culture filtrates and mycelia, respectively. The native compounds epicatechin, catechin, phloridzin, chlorogenic acid, caffeic acid, p-coumaric acid and phloridzin tested under non-oxidizing conditions had no or weak effects on enzyme activities. A significant inhibition of pectinase was only detected with the highest concentrations of procyanidins and phloretin. Aerobe conditions resulted in a fast oxidation of most phenolics which was enhanced by fungal phenoloxidases. Generally, no inhibition of fungal growth occurred in vitro but distinct irreversible effects on proteins and enzymes were detected with oxidized phenolics in course of in vitro-cultures as well as with the corresponding preparations. Efficacy of inhibitory activity in in vitro-cultures depended on media, culture technique and time course. Direct treatment of enzyme preparations with the oxidized phenolics resulted in a distinct inhibition of cellulolytic and especially pectinolytic activity. Apart from cellulase pattern altered by phenolics, in vitro-culture zymograms revealed a non specific reduction of enzymatic activities, whereas action on total culture filtrate proteins resulted in specific effects due to phenolic compounds and incubation time. An attempt was made to characterize the oxidation products of epicatechin. Chromatographic fractionation revealed a non-resolvable complex of inhibitory compounds which were not consistent with the typical yellow oxidation products.     

Determination of procyanidins and their metabolites in plasma samples by improved liquid chromatography–tandem mass spectrometry

An off-line solid-phase extraction (SPE) and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining procyanidins, catechin, epicatechin, dimer, and trimer in plasma samples. In the validation procedure of the analytical method, linearity, precision, accuracy, detection limits (LODs), quantification limits (LOQs), and the matrix effect were studied. Recoveries of the procyanidins were higher than 84%, except for the trimer, which was 65%. The LODs and LOQs were lower than 0.003 and 0.01 μM, respectively, for all the procyanidins studied, except for the trimers, which were 0.8 and 0.98 μM, respectively. This methodology was then applied for the analysis of rat plasma obtained 2 h after ingestion of grape seed phenolic extract. Monomers (catechin and epicatechin), dimer and trimer in their native form were detected and quantified in plasma samples, and their concentration ranged from 0.85 to 8.55 μM. Moreover, several metabolites, such as catechin and epicatechin glucuronide, catechin and epicatechin methyl glucuronide, and catechin and epicatechin methyl-sulphate were identified. These conjugated forms were quantified, in reference to the respective unconjugated form, showing concentrations between 0.06 and 23.90 μM.     

金刺梨果实和叶中酚类、Vc含量及其抗氧化能力分析

为了解贵州金刺梨（Rosa sterilis D.Shi）果实和叶片中的活性成分及其抗氧化活性,以贵州普定县金刺梨种植基地的果实和叶片为试材,测定其活性成分含量及其抗氧化活性,并对各项指标进行相关性分析。结果显示：没食子酸、芦丁、槲皮素、儿茶素、鞣花酸、绿原酸、阿魏酸是供试金刺梨果实和叶片的主要酚类成分,金刺梨果实和叶片中活性组分差异显著（P<0.05）,果实中p-香豆酸、总黄酮和抗坏血酸的含量相对较高,而叶片中没食子酸、儿茶素、绿原酸、表儿茶素、阿魏酸、鞣花酸、芦丁、槲皮素和总酚含量均高于果实;金刺梨果实抗氧化活性值均显著高于叶片（P<0.05）;相关性分析发现：总黄酮对总还原力（TRPA）值的贡献极强,抗坏血酸对Fe³⁺还原抗氧化能力（FRAP）值贡献最强,槲皮素对ABTS值的贡献最强,说明金刺梨果实和叶片是一种具有较高开发价值的药食同源资源。     

Identification of naturally occurring calmodulin inhibitors in plants and their effects on calcium- and calmodulin-promoted protein phosphorylation

While studying the calmodulin activity in post-climacteric apples, a heat stable, dialyzable component that inhibited calmodulin-promoted phosphodiesterase activity was detected. The compound(s) that inhibited calmodulin activity did not bind to Dowex-50, H+ or Dowex-2, Cl- and was exclusively present in the neutral fraction. The inhibitors irreversibly bound to polyvinylpolypyrrolidone indicating their phenolic nature. Fractionation of the neutral fraction on a C18-microbondapak column and analysis for the inhibition of calmodulin-promoted phosphodiesterase activity showed significant inhibitory activity associated with fractions eluted 5 min, 15 min and 18 min after injection. Perdeuteriomethylation and combined gas chromatographic-mass spectrometric analysis of the inhibitors showed them to be flavonoids. (+)-Catechin was identified in the fraction eluted 5 min after injection that also showed maximum inhibition. Other flavonoids such as epicatechin, quercetin and naringenin also inhibited calmodulin-promoted phosphodiesterase activity. Among the phenolic compounds commonly encountered in plant tissue only caffeic acid inhibited calmodulin-promoted phosphodiesterase activity. Inhibition by catechin and caffeic acid could be reversed by increasing the calmodulin concentration in the assay mixture. Both catechin and caffeic acid inhibited Ca- and calmodulin-promoted phosphorylation of soluble proteins from corn coleoptiles. The physiological properties of flavonoids are discussed in light of this evidence.     

Effects of polyphenols from grape seeds on oxidative damage to cellular DNA

Grape seed polyphenols have been reported to exhibit a broad spectrum of biological properties. In this study, eleven phenolic phytochemicals from grape seeds were purified by gel chromatography and high performance liquid chromatography (HPLC). The antioxidant activities of five representative compounds with different structure type were assessed by the free radical-scavenging tests and the effects of the more potent phytochemicals on oxidative damage to DNA in mice spleen cells were investigated. Procyanidin B4, catechin, epicatechin and gallic acid reduced ferricyanide ion and scavenged the stable free radical, alpha, alpha-diphenyl-beta-picrylhydrazyl (DPPH) much more effectively than the known antioxidant vitamin ascorbic acid, while epicatechin lactone A, an oxidative derivative of epicatechin, did not reduce ferricyanide ion appreciably at concentrations used and was only about half as effective on free radical-scavenging as epicatechin. Mice spleen cells, when pre-incubated with relatively low concentration of procyanidin B4, catechin or gallic acid, were less susceptible to DNA damage induced by hydrogen peroxide (H2O2), as evaluated by the comet assay. In contrast, noticeable DNA damage was induced in mice spleen cells by incubating with higher concentration (150 microM) of catechin. Collectively, these data suggest that procyanidin B4, catechin, gallic acid were good antioxidants, at low concentration they could prevent oxidative damage to cellular DNA. But at higher concentration, these compounds may induce cellular DNA damage, taking catechin for example, which explained the irregularity of dose-effect relationship.     

Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5

A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a–v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC₅₀ value of 13.2?µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC₅₀ of 17.2?µM and 20.2?µM, respectively. A brief structure–activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein–ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a–v were also calculated based on the Lipinski’s rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development.     

Polyamine derivatives from the bee pollen of Quercus mongolica with tyrosinase inhibitory activity

Eighteen constituents, including nine new compounds, were isolated from the bee pollen of Quercus mongolica. The structures of the new compounds were established on the basis of combined spectroscopic analysis. Structurally, the nine new compounds are polyamine derivatives with phenolic moieties which were assigned as one putrescine derivative, mogolicine A (2), seven spermidine derivatives, mongolidines A-G (3–5, 8, 12, 14, 17) and one spermine derivative, mogoline A (18). Evaluation of the biological activity of isolated compounds revealed that the polyamine derivatives with coumaroyl and caffeoyl moieties showed tyrosinase inhibition with IC₅₀ values of 19.5–85.8 μM; however, the addition of a methoxy group to phenolic derivatives reduced the inhibitory activity.     

Anticancer and DNA binding studies of potential amino acids based quinazolinone analogs: Synthesis,SAR and molecular docking

A novel series of amino acids conjugated quinazolinone-Schiff’s bases were synthesized and screened for their in vitro anticancer activity and validated by molecular docking and DNA binding studies. In the present investigations, compounds 32, 33, 34, 41, 42 and 43 showed most potent anticancer activity against tested cancer cell lines and DNA binding study using methyl green comparing to doxorubicin and ethidium bromide as a positive control respectively. The structure-activity relationship (SAR) revealed that the tryptophan and phenylalanine derived electron donating groups (OH and OCH₃) favored DNA binding studies and anticancer activity whereas; electron withdrawing groups (Cl, NO₂, and F) showed least anticancer activity. The molecular docking study, binding interactions of the most active compounds 33, 34, 42 and 43 stacked with A–T rich regions of the DNA minor groove by surface binding interactions were confirmed.     

Synthesis and evaluation of novel 7-azaindazolyl-indolyl-maleimide derivatives as antitumor agents and protein kinase C inhibitors

A series of novel 7-azaindazolyl-indolyl-maleimides were synthesized and evaluated for their antiproliferative activity in vitro against various human cancer cell lines and protein kinase C inhibitory activity. Compounds 8a–c, 8e and 14a were the most promising compounds against K562, A549, ECA-109, KB and SMMC-7721 cell lines in vitro. Compounds 9a–j showed moderate PKC inhibition. Further mechanism of action studies revealed that the antiproliferative activity of compound 8b in KB cells might involve the mitochondria-mediated apoptosis pathway.     

Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis

We isolated 18 polyphenols with neuraminidase inhibitory activity from methanol extracts of the roots of Glycyrrhiza uralensis. These polyphenols consisted of four chalcones (1–4), nine flavonoids (5–13), four coumarins (14–17), and one phenylbenzofuran (18). When we tested the effects of these individual compounds and analogs thereof on neuraminidase activation, we found that isoliquiritigenin (1, IC₅₀ = 9.0 μM) and glycyrol (14, IC₅₀ = 3.1 μM) had strong inhibitory activity. Structure–activity analysis showed that the furan rings of the polyphenols were essential for neuraminidase inhibitory activity, and that this activity was enhanced by the apioside group on the chalcone and flavanone backbone. In addition, the presence of a five-membered ring between C-4 and C-2′ in coumestan was critical for neuraminidase inhibition. All neuraminidase inhibitors screened were found to be reversible noncompetitive inhibitors.     

Click approach to the discovery of 1,2,3-triazolylsalicylamides as potent Aurora kinase inhibitors

A series of 1,2,3-triazolylsalicylamide derivatives has been developed from the antiproliferative agent 7 and was evaluated for their Aurora kinase inhibitory activity. The novel 1,2,3-triazolylsalicylamide scaffold could be readily assembled by Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition, allowing rapid access to the structurally diverse analogues. The synthesized 1,2,3-triazolylsalicylamide derivatives revealed a significant Aurora kinase inhibitory activity. In particular, 8g inhibited Aurora A with IC₅₀ values of 0.37 μM. The critical role of phenolic –OH in the binding was confirmed by a molecular modeling study.     

The influence of wine polyphenols on reactive oxygen and nitrogen species production by murine macrophages RAW 264.7

The aim was to study the antioxidant properties of four wine polyphenols (flavonoids catechin, epicatechin, and quercetin, and hydroxystilbene resveratrol). All three flavonoids exerted significant and dose-dependent scavenging effects against peroxyl radical and nitric oxide in chemical systems. The scavenging effect of resveratrol was significantly lower. All polyphenols decreased production of reactive oxygen species (ROS) by RAW264.7 macrophages. Only quercetin quenched ROS produced by lipopolysaccharide-stimulated RAW264.7 macrophages incubated for 24 h with polyphenols. Quercetin and resveratrol decreased the release of nitric oxide by these cells in a dose-dependent manner which corresponded to a decrease in iNOS expression in the case of quercetin. In conclusion, the higher number of hydroxyl substituents is an important structural feature of flavonoids in respect to their scavenging activity against ROS and nitric oxide, while C-2,3 double bond (present in quercetin and resveratrol) might be important for inhibition of ROS and nitric oxide production by RAW 264.7 macrophages.     

Enhancement of phagocytic activity of macrophage-like cells by pyrogallol-type green tea polyphenols through caspase signaling pathways

We investigated the phagocytosis-enhancing activity of green tea polyphenols, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin (EC) catechin (+C) and strictinin, using VD3-differentiated HL60 cells. EGCG, EGC, ECG and strictinin, but not EC and +C, increased the phagocytic activity of macrophage-like cells, and a caspase inhibitor significantly inhibited phagocytic activities. These results suggest that the pyrogallol-type structure in green tea polyphenols may be important for enhancement of the phagocytic activity through caspase signaling pathways.     

N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells

A series of N-acyl derivatives of tyramine, tryptamine, and serotonin were synthesized and tested on anti-melanogenic activity. The serotonin derivatives such as N-caffeoylserotonin (3) and N-protocatechuoylserotonin (9) were inhibitory to tyrosinase from mouse B16 and human HMV-II melanoma cells, while the corresponding derivatives of tryptamine and 5-methoxytryptamine were almost inactive or less active than the serotonin derivatives. The inhibitory activity of the serotonin derivatives increased with increasing number of phenolic hydroxyl groups in the acyl moiety. Melanin formation in the culture of B16 cells was suppressed by 3 and 9 with no cytotoxicity in the concentration range tested (IC₅₀ = 15, 3 and 111 μM for 3, 9, and kojic acid, respectively). Thus the N-acylserotonin derivatives having a dihydroxyphenyl group are potential anti-melanogenic agents. Their inhibition of tyrosinase is primarily performed through the 5-hydroxyindole moiety and further strengthened by the phenolic hydroxyl groups in the acyl moiety.