Mechanochemical activation with cyclodextrins followed by compaction as an effective approach to improving dissolution of rutin.

Rutin is one of the most important flavonoids with poor bioavailability. This work aimed at addressing the issue of poor biopharmaceutical performance of rutin by applying a combination of complexation with secondary processing into tablets. Mechanical activation was the most suitable method of rutin complex formation with (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD), while the ß-cyclodextrin (ß-CD) complex successfully formed by kneading with an ethanol/water mixture. Complexation was confirmed by thermal analysis, powder X-ray diffraction and vibrational spectroscopy. Dynamic vapour sorption showed that stability of powders at high humidity conditions was satisfactory, however, the ß-CD complex retained around 8% of moisture. The complexes were compacted with or without tricalcium phosphate (TRI-CAFOS) filler at a range of compression pressures (19-113 MPa). The best tabletability was determined for rutin/HP-ß-CD, compressibility for the TRI-CAFOS blends with complexes and compactibility for the rutin/HP-ß-CD + TRI-CAFOS mix. Dissolution studies showed quicker and more complete dissolution (pH 1.2) of rutin/HP-ß-CD tablets, however the compacts comprising the filler were superior than pure complexes. The tablets manufactured in this study appear to be promising delivery systems of rutin and it is recommended to combine rutin/HP-ß-CD with TRI-CAFOS and compact at 38-76 MPa.

Chitosan coated chlorogenic acid and rutincomposite phospholipid liposomes: Preparation, characterizations, permeability and pharmacokinetic.

In order to research and enhance bioavailability of chlorogenic acid and rutin(CA-R) via the oral route, chitosan coated composite phospholipid liposomes (C-CPLs) were applied to study on preparation, permeability and pharmacokinetic of C-CA-R-CPLs. TheC-CA-R-CPLs were prepared by the method of ethanol injection. The entrapment efficiency (EE), average particle sizes, polymer disperse index (PDI), zeta potential, shape and in vitro drug release were investigated to characterize physicochemical parameters of C-CA-R-CPLs. The penetration properties from C-CA-R-CPLs were studied through Caco-2 cells model and the pharmacokinetics in Sprague-Dawley (SD) rats were evaluated by rat jugular vein intubation tube. The EE of C-CA-R-CPLs of CA and R was 91.3±2.13% and 92.6±2.44%, particle size of C-CA-R-CPLs was 176.7±2.3 nm, PDI was 0.207±0.014 and zeta potential of 12.61±1.33 mV. CA-R-CPLs and C-CA-R-CPLs were spherical or elliptical sphere and the bilayer of the CPL was observed obviously under transmission electron. The Cmax, t1/2 and AUC0-12 h values of CA and R for groups of C-CA-R-CPLs were significantly increased.In conclusion, TheC-CA-R-CPLs as a novel nano-formulation have potential to be used to enhance the oral bioavailability of poorlywater-soluble drugs after oral administration.

Rutin-Nickel Complex: Synthesis, Characterization, Antioxidant, DNA Binding, and DNA Cleavage Activities.

The rutin-nickel (II) complex (RN) was synthesized and characterized by elemental analysis, UV-visible spectroscopy, IR, mass spectrometry, 1H NMR, TG-DSC, SEM, and molar conductivity. The low molar conductivity value investigates the non-electrolyte nature of the complex. The elemental analysis and other physical and spectroscopic methods reveal the 1:2 stoichiometric ratio (metal/ligand) of the complex. An antioxidant study of rutin and its metal complex against DPPH radical showed that the complex has more radical scavenging activity than free rutin. The interaction of complex RN with DNA was determined using fluorescence spectra and agarose gel electrophoresis. The results showed that RN can intercalate moderately with DNA, quench a strong intercalator ethidium bromide (EB), and compete for the intercalative binding sites. The complex showed significant cleavage of pBR 322 DNA from supercoiled form (SC) to nicked circular form (NC), and these cleavage effects were dose-dependent. Moreover, the mechanism of DNA cleavage indicated that it was a hydrolytic cleavage pathway. These results revealed the potential nuclease activity of the complex to cleave DNA.

Design, synthesis, and antiviral activity of novel rutin derivatives containing 1, 4-pentadien-3-one moiety.

Rutin (compound 5) and some compounds (compounds 1-4 and 6) were isolated from Artemisia princeps Pamp (A. princeps Pamp.) and a series of novel rutin derivatives containing 1,4-pentadien-3-one moiety were designed and synthesized. The target compounds were characterized by proton nuclear magnetic resonance spectroscopy ((1)H NMR), carbon nuclear magnetic resonance spectroscopy ((13)C NMR), and ESI-MS. Bioassay results indicated that some of the compounds showed good to excellent antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) at 500 µg/mL in vivo. The 50% effective concentrations (EC50) of the compound 7r against CMV was 394.78 µg/mL, which was better than that of Ningnanmycin (432.22 µg/mL). These results indicated that novel rutin derivatives containing 1,4-pentadien-3-one moiety can effectively control CMV.

Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties.

Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis.

Monoglucosyl-rutin as a potential radioprotector in mammalian cells.

In the present study, the role of monoglucosyl­rutin as a potential radioprotector was investigated using mammalian cell culture models. Cell survival and DNA damage were assessed using colony formation, sister chromatid exchange and γH2AX assays. It was demonstrated that monoglucosyl­rutin was able to increase cell survival when exposed to ionizing radiation, possibly by decreasing the amount of base damage experienced by the cell. However, the present study also demonstrated that, despite monoglucosyl­rutin exhibiting radioprotective effects at low doses, high doses of monoglucosyl­rutin led to a decrease in plating efficiency and an increased doubling time. This effect may be due to double­strand breaks caused by high concentrations of monoglucosyl­rutin.

[Synthesis and identification of rutin complete antigen and analysis its immunogenicity].

OBJECTIVE: Synthesis and identification of complete antigen of rutin, the traditional Chinese medicine active ingredient, and develop rapid detection of rutin using enzyme-linked immunoassay method (ELISA). Immunogenicity of the complete antigen was also studied. METHOD: Prepare the complete antigen by sodium periodate solution and identified by UV scanning and SDS-PAGE test. Male New Zealand white rabbits were immunized by the antigen to obtain the antiserum. RESULT: The results of UV analysis showed that the coupling ratio of complete antigen is 13: 1. SDS-PAGE display of the artificial antigen was delayed compared with bovine serum protein. The titer of rutin antibody is 1:4 000. The sensitivity of IC50 was 5.37 mg x L(-1), the lowest detection limit was 1 mg x L(-1), the average recovery was 102%, the intra and interspecific RSD were less than 10%, cross-reactivity rate of antibodies and other analogs were less than 1%. CONCLUSION: Rutin complete antigen was synthesized successfully, and the rapid detection of rutin by ELISA method was successfully established.

Síntese e avaliação da segurança in vitro da rutina e do succinato de rutina visando sua incorporação em formulações fotoprotetoras eficazes associados a filtros químicos e físico / Synthesis and in vitro safety evaluation of rutin and rutin succinate aiming their incorporation into effective sunscreens associated with chemical and physical filters

A tendência atual do mercado cosmético é desenvolver produtos que contenham insumos de origem vegetal. O objetivo deste trabalho foi a aplicação da Tecnologia da Química Verde na síntese da rutina visando o aumento da estabilidade dessa em formulações cosméticas com sua eficácia antioxidante e fotoprotetora. Realizou-se a síntese química por meio da introdução de grupos carboxilatos às hidroxilas do dissacarídeo na molécula de rutina, gerando como produto final o succinato de rutina. Este derivado e/ou a rutina foram incorporados em 74 formulações-teste e, selecionadas 12 (sistemas emulsionados O/A), após serem submetidas à Avaliação Preliminar de Estabilidade (APE) e ao Teste de Estabilidade Acelerada (TEA), sob variações de temperatura e umidade. Utilizou-se agentes emolientes e silicones para facilitar a solubilização e/ou dispersão dos filtros químicos e físicos. A segunda etapa deste trabalho foi a avaliação da segurança do succinato de rutina, tendo como padrão a rutina, por meio do método alternativo de toxicidade in vitro, o XTT. Após o screening das concentrações ensaiadas, as que apresentaram menor nível de morte celular foram respectivamente, 0,1% ou 1 mg/mL (rutina) e 0,4% ou 4 mg/mL (succinato de rutina). Segundo os resultados do TEA, as formulações contendo succinato de rutina associada ou não aos filtros solares em ambas as bases cosméticas (A - Crodafos®CES + Uniox®C e B - Hostacerin®SAF) foram selecionadas para a continuidade do Teste de Estabilidade Normal (TEN). Neste teste, as emulsões fotoprotetoras foram avaliadas frente aos parâmetros: propriedades organolépticas (aspecto, cor e odor), aspectos físico-químicos (medição de pH e de viscosidade) e funcionais (atividade antirradicalar e eficácia fotoprotetora in vitro). Os resultados apresentados pela formulação MS (succinato de rutina associado aos filtros químicos e físico) foram: homogeneidade, a não modificação de cor e odor em temperatura ambiente, a não alterações significativas...

The current cosmetic market trend is to develop products containing vegetables raw materials. This work proposed to use the Technology of Green Chemical to increase the rutin stability in cosmetic formulas as regards of its antioxidant and photoprotective properties. The chemical synthesis was realized by the introduction of carboxylate groups on sugar moiety of rutin producing in rutin succinate. This derivative and/or rutin were incorporated into 74 test formulas. After the undergoing to preliminary and accelerated stabilities under different temperature and humidity conditions were selected 12 formulas (O/W emulsions). Emollient agents and silicones were used to improve the solubility and/or dispersion of the chemical and physical filters. The second stage of this work was to evaluate the safety of rutin succinate, rutin used as an internal standard, using the alternative method of in vitro toxicity, the XTT. After the screening of tested concentrations, the concentrations of the samples with the lowest level of cell death were 0.1% or 1 mg/mL (rutin) and 0.4% or 4 mg/mL (rutin succinate), respectively. According to results obtained in accelerated stability testing, the formulations containing rutin succinate in combination or not with UV filters in both O/W emulsions (A - Crodafos®CES + Uniox®C and B - Hostacerin®SAF) were selected for the long term stability test. In this test the sunscreens were evaluated in the following parameters: the organoleptic properties (appearance, color and odor), physico-chemical aspects (pH value and viscosity) and functional (antiradicalar activity and in vitro photoprotection efficacy). The results presented by the MS formula (rutin succinate associated with physical filter and chemical filters) were: uniformity, stability of color and odor at room temperature and showed no significant difference, as well stability in: pH and SPF (Sun Protection Factor) values, hysteresis area, antiradicalar activity. These results were...

Flavonoids with an oligopolysulfated moiety: a new class of anticoagulant agents.

Polysulfated (oligo)flavonoids were synthesized and assayed for their in vitro and in vivo anticoagulant activities. The approach was based on molecular hybridization of two classes of anticoagulants, sulfated polysaccharides and sulfated flavonoids. The synthesis was optimized using microwave-assisted sulfation with triethylamine-sulfur trioxide. The obtained polysulfated flavonosides were highly effective in increasing clotting times and able to completely block the clotting process, in contrast to their corresponding aglycones. The thromboelastography proved that polysulfated flavonosides possess good whole blood anticoagulation activity. The following structure-activity relationships were found: 3-O-rutinosides (10, 13) were direct inhibitors of FXa, while 7-O-rutinosides (7, 8) showed inhibition of FXa by ATIII activation. Furthermore, compounds 7 and 13 were stable in plasma and active in vivo and preliminary toxicity studies would lead us to rule out acute side effects. From the overall results, the polysulfated flavonosides showed the potential as new effective and safe agents for anticoagulant therapy.

[Synthesis and characterization of some new rutin and 7-aminocephalosporanic acid derivatives]. / Sinteza si caracterizarea unor noi derivati ai rutozidului cu acid 7-amino-cefalosporanic.

UNLABELLED: Many studies show that flavonoids have a numerous biological properties, antimicrobial effects included. It is also known that rutin is able to increase the antibacterial activity of other compounds. MATERIAL AND METHODS: Starting from these facts, we synthesised some water soluble rutin derivatives treating rutin with 1, 3-dichloro-2-propanol, 1-bromo-3-chloro-propane, 2-dibromethane, and dibrommethane, and than with 7-amino-cephalosporanic acid. The antimicrobial activity of the new compounds was determined by disc diffusion method. RESULTS: Molecular formula, weight, yield, melting points and solubility of the new derivatives have been determined. Elemental analysis and spectral analysis (UV and IR) confirmed the structure of new compounds. CONCLUSIONS. These derivatives are water-soluble and have a good antimicrobial activity, both on Gram-positive and Gram-negative bacteria, comparable with that of tetracycline.

Monolayers of mixture of alkylaminomethyl rutin and lecithin at the air/water interface.

A compound of flavonol-based biosurfactant, as C(8)-substituted alkylaminomethyl rutin (DAMR) for a potential pharmaceutical or agrochemical use, was prepared experimentally. The surface behavior of DAMR and its mixture with lecithin from soybean (SL) had been studied. DAMR, regarded as a pseudo-amphoteric character, exhibits both liquid-condensed (LC) and liquid-expanded (LE) phases while SL is in the form of the LE phase only. The phase parameters of DAMR (including A(limt), pi(coll)) are observed to strongly depend on both the subphase temperature and the pH, which regulate the degree of ionization. In addition, the observed positive deviation calculated from excess Gibbs free energies of the DAMR-SL system suggests a repulsive interaction between DAMR and SL at all X(DAMR) values. Also the interaction parameter is found to increase linearly with surface pressure, regardless of composition. Notably, the relationship of logarithmic activity coefficient vs. X(DAMR)(2) reveals that the molecular interaction of DAMR-SL can be adequately simulated using a simple regular mixture model. Importantly, lower C(S)(-1) values of this mixture than those with pure DAMR and SL denote weak elasticity of mixed monolayers with values of X(DAMR) of 0.2-0.8, indicating that the direct addition of DAMR may exert a somewhat adverse influence on SL membranes.

[Research concerning rutin semisynthetic derivatives. Synthesis, physico-chemical and microbiological characterisation of some new rutin-isoniazid derivatives]. / Cercetari in seria derivatilor de semisinteza ai rutozidului. Sinteza si caracterizarea fizico-chimica si microbiologica a unor noi compusi ai rutozidului cu izoniazida.

UNLABELLED: Isoniazid is one of the most used antituberculosis drugs, but its toxicity is high. In this study, four derivatives of rutin and isoniazid were prepared and their antibacterial and antimycotic activities were investigated. METHOD: Synthesis of these compounds started through reaction of rutin with fresh prepared sodium methoxide, subsequently treating with 1, 3-dichloro-2-propanol, 1-brom-3-chloropropane, 1, 2-dibrom-ethane or dibrommethane and finally, stirring with isoniazid, to afford crystalline, yellow, water soluble powders. RESULTS: The four compounds were marginally active against Staphylococcus aureus and Staphylococcus saprophyticus and were inactive against Escherichia coli. CONCLUSION: We synthesised four new derivatives of rutin and isoniazid; melting points, solubility, yields characterised these compounds, and their structure was confirmed by C, H, N elemental analysis and UV spectra. The compounds showed a modest antibacterial activity. We think that the toxicity of the new derivatives will be lower that of isoniazid toxicity. The next steps in our research will be the toxicological study and antituberculosis assay.

[Synthesis and physico-chemical characterisation of some new derivatives of rutoside and clofibric acid]. / Sinteza si caracterizarea fizico-chimica a unor noi compusi ai rutozidului cu acidul clofibric.

Fibrates are drugs with efficacy in reducing blood cholesterol levels and especially, triglyceride plasma levels. Unfortunately, fibrates have a poor water-solubility and showed some adverse reactions at long treatment. The objective of this study was to obtain some new clofibric acid derivatives with rutin; some of these compounds contain a guanidine moiety, known as effective at cardiovascular level. All the compounds are soluble in water.

Rutoxyl [rutin/4-acetamide-1-hydroxy-2,2,6,6-tetramethylpiperidinium] is a new member of the class of semi-natural products of high pharmacological potency.

A novel complex, Rutoxyl [rutin/4-acetamide-1-hydroxy-2,2,6,6-tetramethylpiperidinium] was synthesized and its structure and anticancer activity were investigated. The results reported here are consistent with our idea, that the formation of such a complex of two biologically active molecules: polyphenolic flavonoid antioxidant (Rutin) and nitroxylamine of nitroxide antioxidant (Tempace), stabilized by hydrogen bond(s) can result in a supra-additive properties.

Enzymatic synthesis of butyryl-rutin ester in organic solvents and its cytogenetic effects in mammalian cells in culture.

Enzymic acylation of a flavonoid, rutin, with trichloroethylbutyrate (TCEB) has been performed by subtilisin protease in anhydrous pyridine solution. The addition of a hydrophobic compound on rutin is expected to change the hydrophilic/hydrophobic balance of the molecule, giving new properties to this compound. This work aimed at investigating the various cytological properties of the rutin-ester and compared them with those of the native molecule. No difference in the levels of sister chromosomes exchange (SCE) between rutin and rutin-ester treated cells at doses varying from 25 to 200 micrograms/mL was found. On the contrary impressive difference in the induced frequency of micronuclei (MN) between rutin and rutin ester treated cells was observed, for example, at a dose of 100 micrograms/mL of rutin were 3.5% MN counted, whereas for a similar dose treatment with rutin-ester a frequency of 8% of MN was found. The fact that rutin-ester is causing significantly higher levels of MN than the rutin alone can be considered as a manifestation of a higher action of the agent on the chromosome owing to its easier penetration in to the cell after its esterification.