Surface modification of poly(2‐hydroxyethyl methacrylate) hydrogel for contact lens application

The present study examined poly(2‐hydroxyethyl methacrylate) (PHEMA)‐based hydrogels that have been extensively used in biomedical applications, including contact lens. In this research, we aimed to reduce adsorption of protein components from tears and bacterial deposition by surface modification of the hydrogel with different functional groups that included carboxylic acid, primary amine, and quaternary ammonium. The PHEMA was treated with a solution of sulfuric acid for partial hydrolysis of the HEMA ester groups to induce acid groups on the surface of the hydrogel. Carboxylic acid groups of the modified PHEMA were converted to primary amine and quaternary ammonium groups via carbodiimide chemistry. The surface physical and chemical properties of different samples were investigated by atomic force microscopy and X‐ray photoelectron spectroscopy, respectively. We conducted the bicinchoninic acid assay to evaluate protein deposition from artificial tear fluid on samples. Antibacterial properties of the modified hydrogels were investigated with a culture of Staphylococcus aureus, one of the major causes of eye infections. Our data showed that positively charged amine and ammonium groups efficiently resisted protein adsorption and bacterial deposition compared to alcohol and carboxylic acid groups.     

Enzyme Deposition by Polydimethylsiloxane Stamping for Biosensor Fabrication

High‐performance biosensors were fabricated by efficiently transferring enzyme onto Pt electrode surfaces using a polydimethylsiloxane (PDMS) stamp. Polypyrrole and Nafion were coated first on the electrode surface to act as permselective films for exclusion of both anionic and cationic electrooxidizable interfering compounds. A chitosan film then was electrochemically deposited to serve as an adhesive layer for enzyme immobilization. Glucose oxidase (GOx) was selected as a model enzyme for construction of a glucose biosensor, and a mixture of GOx and bovine serum albumin was stamped onto the chitosan‐coated surface and subsequently crosslinked using glutaraldehyde vapor. For the optimized fabrication process, the biosensor exhibited excellent performance characteristics including a linear range up to 2 mM with sensitivity of 29.4±1.3 μA mM⁻¹ cm⁻² and detection limit of 4.3±1.7 μM (S/N=3) as well as a rapid response time of ∼2 s. In comparison to those previously described, this glucose biosensor exhibits an excellent combination of high sensitivity, low detection limit, rapid response time, and good selectivity. Thus, these results support the use of PDMS stamping as an effective enzyme deposition method for electroenzymatic biosensor fabrication, which may prove especially useful for the deposition of enzyme at selected sites on microelectrode array microprobes of the kind used for neuroscience research in vivo .     

Pt Nanoparticle‐modified Carbon Fiber Microelectrode for Selective Electrochemical Sensing of Hydrogen Peroxide

We report a simple approach to the production of carbon fiber‐based amperometric microbiosensors for selective detection of hydrogen peroxide (H₂O₂), which was achieved by electrometallization of carbon fiber microelectrodes (CFMs) by electrodeposition of Pt nanoparticles. The Pt‐carbon hybrid sensing interface provided a sensitivity of 7711±587 μA ? mM^?1 ? cm^?2, a detection limit of 0.53±0.16 μM (S/N=3), a linear range of 0.8 μM–8.6 mM, and a response time of <2 sec. The morphologies of the Pt nanoparticle‐modified CFMs were characterized by scanning electron microscopy. To achieve selectivity, permseletive layers, polyphenylenediamine (PPD) and Nafion, were deposited resulting in exclusion of the anionic and cationic interferents, ascorbic acid and dopamine, respectively, at their physiologically relevant concentrations. The resultant sensors displayed a sensitivity to hydrogen peroxide of 1381±72 μA ? mM^?1 ? cm^?2, and a detection limit of 0.86±0.19 μM (S/N=3). This simple and rapid metallization method converts carbon fiber microelectrodes, which are readily accessible, to microscale Pt electrodes in 2 min, providing a platform for oxidase‐based amperometric biosensors with improved spatial resolution over more commonly used platinum electrode array microprobes.     

Influence of gel composition on the solubility parameter of poly(2‐hydroxyethyl methacrylate‐itaconic acid) hydrogels

The solubility parameters of pure poly(2‐hydroxyethyl methacrylate) (PHEMA) and poly(2‐hydroxyethyl methacrylate/itaconic acid) [P(HEMA/IA)] hydrogels were determined by 20 solvents with various solubility parameters in swelling experiments. The solubility parameter of pure PHEMA was 26.93 ± 0.46 (MPa)^1/2. The effect of mole percentages of itaconic acid (IA) in P(HEMA/IA) hydrogels on the solubility parameter was investigated. The measured values were compared to literature and solubility values theoretically determined by group contribution values of van Krevelen and Hoy. The incorporation of IA into the hydrogel system slightly increased the solubility parameter. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 1995–2003, 2002     

pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

A pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2080–2095     

Determination of Labetalol Hydrochloride in Drug Formulations by Spectrophotometry

A validated, selective and sensitive spectrophotometric method has been developed for the determination of labetalol hydrochloride in commercial dosage forms. The method is based on the coupling reaction of positive diazonium ion of 4‐aminobenzenesulfonic acid with phenolate ion of labetalol to form a colored azo compound which absorbs maximally at 395 nm. Under the optimized experimental conditions, the color is stable up to 2 h and Beer's law is obeyed in the concentration range of 0.8–17.6 μg mL^?1 with a linear regression equation of A = 4.84 × 10^?4 + 7.864 × 10^?2 C and coefficient of correlation, r = 0.9999. The molar absorptivity and Sandell's sensitivity are found to be 2.874 × 10⁴ L mol^?1 cm^?1 and 0.013 μg cm^?2 per 0.001‐absorbance unit, respectively. The limits of detection and quantitation of the proposed method are 0.08 and 0.23 μg mL^?1, respectively. The intra‐day and inter‐day precision variation and accuracy of the proposed method is acceptable with low values of standard analytical error. The recovery results obtained by the proposed method in drug formulations are acceptable with mean percent recovery ± RSD of 99.97 ± 0.52 ‐ 100.03 ± 0.63%. The results of the proposed method compared with those of Bilal's spectrophotometric method indicated excellent agreement with acceptable true bias of all samples within ± 2.0%.     

Electrooxidation and Amperometric Detection of Ascorbic Acid at GC Electrode Modified by Electropolymerization of N,N‐Dimethylaniline

The polymer film of N,N‐dimethylaniline (DMA) is deposited on the electrochemically pretreated glassy carbon (GC) electrode by continuous electrooxidation of the monomer. This poly N,N‐dimethylaniline (PDMA) film‐coated electrode can be used as an amperometric sensor of ascorbic acid (AA). The polymer film (thickness (?): 0.3±0.02 μm) having positive charge in its backbone attracts the anionic species AA. Thus, the anodic peak potential (350 mV vs. Ag|AgCl|NaCl_(sat)) for the oxidation of AA at the bare electrode is largely shifted to the negative value (150 mV) at this electrode. The PDMA film‐coated electrode is stable in acidic, alkaline and neutral media and can sense AA at different pH's. The diffusion coefficients of AA in solution (D) and in film (D_s) were estimated by rotating disk electrode voltammetry: D=(5.5±0.1)×10^?6 cm² s^?1 and D_s=(6.3±0.2)×10^?8, (6.0±0.2)×10^?8 and (4.7±0.2)×10^?8 cm² s^?1 for 0.5, 1.5 and 3.0 mM AA, respectively. A permeability of AA through the PDMA film was found to decrease with increasing the concentration of AA in the solution. In the chronoamperometry, the current response for the oxidation of AA at different times elapsed after potential‐step application is linearly increased with the increase in AA concentration in a wide range of its concentration from 25 μM to 1.65 mM. In the hydrodynamic amperometry, a successive addition of 10 μM AA caused the successive increase in current response with equal amplitude and the sensitivity was calculated as 0.178 μA cm^?2 μM^?1. So, the fouling of the electrode surface caused by the oxidized product of AA is markedly eliminated at this PDMA film‐coated electrode. A flow injection analysis based on the present electrode was performed to estimate the concentration of vitamin C in fruit juice.     

Properties of poly(dimethylsiloxane)/hydrogel multicomponent systems

The properties of surface‐ and bulk‐modified poly(dimethylsiloxane) (PDMS) were examined. Laser‐induced surface grafting of poly(2‐hydroxyethyl methacrylate) (PHEMA) on PDMS and a sequential method for preparation of interpenetrating polymer networks of PDMS/PHEMA were, respectively, used for surface and bulk modifications. The hydrogel content and water‐uptake capability of the modified samples were also investigated. The modified PDMS samples were examined by performing attenuated total reflection/Fourier transform infrared spectroscopy, dynamic mechanical thermal analysis, scanning electron microscopy, and water contact‐angle measurements. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 2145–2156, 2003     

Mass spectrometry of intact neutral macromolecules using intense non‐resonant femtosecond laser vaporization with electrospray post‐ionization

Intact, nonvolatile, biological macromolecules can be transferred directly from the solid state into the gas phase, in ambient air, for subsequent mass spectral analysis using non‐resonant femtosecond (fs) laser desorption combined with electrospray ionization (ESI). Mass spectral measurements for neat samples, including a dipeptide, protoporphyrin IX and vitamin B12 adsorbed on a glass insulating surface, were obtained using an 800 nm, 70 fs laser with an intensity of 10¹³ W cm⁻². No appreciable signal was detected when atmospheric matrix‐assisted or neat (matrix‐free) fs laser desorption was performed without ESI, indicating neutral desorption. Copyright © 2009 John Wiley & Sons, Ltd.     

Dual crosslinked pH‐ and temperature‐sensitive hydrogel beads for intestine‐targeted controlled release

Novel drug‐loaded hydrogel beads for intestine‐targeted controlled release were developed by using pH‐ and temperature‐sensitive carboxymethyl chitosan‐graft‐poly(N,N‐diethylacrylamide) (CMCTS‐g‐PDEA) hydrogel as carriers and vitamin B₂ (VB₂) as a model drug. The hydrogel beads were prepared based on Ca²⁺ ionic crosslinking in acidic solution and formed dual crosslinked network structure. The structure of hydrogel and morphology of drug‐loaded beads were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The study about swelling characteristics of hydrogel beads indicated that the beads had obvious pH‐ and temperature‐sensitivity. In vitro release studies of drug‐loaded beads were carried out in pH 1.2 HCl buffer solution and pH 7.4 phosphate buffer solution at 37°C, respectively. The results indicated that the dual crosslinked method could effectively control the drug release rate under gastrointestinal tract (GIT) conditions, which was superior to traditional single crosslinked beads. In addition, the effects of grafting percentage, pH value, and temperature on the release behavior of the VB₂ were investigated. The drug release mechanism of CMCTS‐g‐PDEA drug‐loaded beads was analyzed by Peppa's potential equation. According to this study, the dual crosslinked hydrogel beads based on CMCTS‐g‐PDEA could serve as suitable candidate for drug site‐specific carrier in intestine. Copyright © 2009 John Wiley & Sons, Ltd.     

SUPERPOROUS HYDROGELS: FAST RESPONSIVE HYDROGEL SYSTEMS

ABSTRACT

Superporous hydrogels, hydrogels with pore sizes in the range of 100 μm and larger, were synthesized using N-isopropyl-acrylamide (NIPAM) and acrylamide (AM). The superporous hydrogels were synthesized by crosslinking polymerization of monomers in the presence of gas bubbles. The pores of superporous hydrogels were connected to each other to form open capillary channels, which provided fast response to the changes in the environmental temperature. Upon increase in temperature from 10°C to 65°C, the superporous hydrogel made from a monomer solution of NIPAM:AM = 9:1 shrank from the fully swollen state (volume of 36 cm³) to the fully collapsed state (volume of 6.5 cm³) in 72±14 sec. When the temperature was changed back to 10°C, the superporous hydrogel swelled to 36 cm³ in 78±15 sec. This deswelling-swelling cycle was repeated many times without changes in the thermo-reversible property of the superporous hydrogel. The response time of the superporous hydrogels was thousand times faster than that of conventional hydrogels. The fast response of the superporous hydrogels is due to the rapid uptake or exclusion of water molecules through the extensive capillary channels. Because superporous hydrogels still maintain the open capillary structure even after drying, the dried superporous hydrogels can also swell to the equilibrium swelling state within minutes. These fast responsive hydrogels can find many pharmaceutical and medical applications.     

Synthesis of Depo‐Medrol–chitosan hydrogel as new drug slow‐release appliance and investigation of release kinetics by high‐performance liquid chromatography

The present study deals with preparation and optimization of a novel chitosan hydrogel‐based matrix by suspension cross‐linking method for controlled release of Depo‐Medrol. The controlled release of Depo‐Medrol for effective Rheumatoid arthritis disease has become an imperative field in the drug delivery system. In this context, it was intended to optimize loading circumstances by experimental design and also study the release kinetics of Depo‐Medrol entrapped in the chitosan matrix in order to obtain maximal efficiency for drug loading. The optimum concentrations of chitosan (2.5 g), glutaraldehyde (3.05 μL) and Depo‐Medrol (0.1 mg) were set up to achieve the highest value of drug loaded and the most sustained release from the chitosan matrix. In vitro monitoring of drug release kinetic using high‐performance liquid chromatography showed that 73% of the Depo‐Medrol was released within 120 min, whereas remained drug was released during the next 67 h. High correlation between first‐order and Higuchi's kinetic models indicates a controlled diffusion of Depo‐Medrol through the surrounding media. Moreover, recovery capacity >82% and entrapment efficiency of 58–88% were achieved under optimal conditions. Therefore, the new synthesized Depo Medrol–chitosan is an applicable appliance for arthritis therapy by slow release mechanism. Copyright © 2016 John Wiley & Sons, Ltd.     

An Adsorption Procedure for Determining the Level of Organophosphorus Pesticide Residues in Pond Water

Abstract

A procedure for the accumulation of phosphorus-containing degradation products of organophosphorus pesticides from water by elution of ion-associates of dialkylphosphorus anions with tetraphenylarsonium cation adsorbed onto an activated carbon micro-column is described.

Using a 50cm³ sample volume at a concentration of 1 μcm^?3 the average accumulation recoveries (%±S.D.) were 81±11 and 91±8 for diethyl and dimethyl phosphorodithioates, 69±10 and 66±10 for the corresponding phosphorothioates and 33±13 and 13±6 for the analogous phosphates. A decrease in these values was caused by the presence of common inorganic anions and at lower concentrations of the analysed species. At a detection limit of 20 ng cm^?3 the recovery was 20–30%. Despite of low accumulation recoveries the minimum detectable concentration of these anions was decreased below 0.1 ng cm^?3 by handling 1 dm³ sample volumes.

The procedure was applied for the analysis of dialkyl phosphorothioates and dialkyl phosphorodithioates in the water from, three ponds located in an apple orchard before and after seasonal application of organophosphorus pesticides.     

Modified chitosan III,superabsorbency, salt‐ and pH‐sensitivity of smart ampholytic hydrogels from chitosan‐g‐PAN

Polyacrylonitrile (PAN) grafted chitosan was prepared by ceric‐initiated graft polymerization of acrylonitrile onto chitosan in a homogenous medium. The copolymer chitosan‐g‐PAN product was then hydrolyzed to yield a novel smart hydrogel (H‐chitoPAN) with superabsorbing properties. The influence of add‐on values as well as temperature and time of hydrolysis of the initial chitosan‐g‐PAN on swelling behavior of the hydrogel was evaluated in water and various salt solutions. The swelling kinetics of the superabsorbing hydrogel was studied as well. The hydrogels exhibited ampholytic and pH‐sensitivity characteristics. Several sharp swelling changes were observed in lieu of pH variations in a wide range (pH 2–13). The swelling variations were explained according to swelling theory based on the hydrogel chemical structure. Superabsorbency, pH‐ and salt‐sensitivity of the chitosan‐based hydrogel was briefly compared with the classical starch‐based superabsorbent, H‐SPAN. The pH‐reversibility and on–off switching behavior of the intelligent H‐chitoPAN hydrogels makes them good candidates for considering as potential drug carries. Copyright © 2004 John Wiley & Sons, Ltd.     

Surface modification by deposition of IPA plasma and gellan gum/chitosan hybrid hydrogel onto thermoplastic polyurethane for controlled release of N‐acetylcysteine

A thin film system composed of gellan gum and chitosan was fabricated through a combination of polyelectrolyte blend and hybrid hydrogel gelation for controlled release of drug. In this study, precursor isopropyl alcohol (IPA) was used to plasma deposit on the surface of thermoplastic polyurethane (TPU) to form a hydrophilic film. The features of the thin film were evaluated using water contact angle (WCA) measurement, scanning electron microscopy (SEM), Fourier transform infra‐red (FTIR), UV/Vis spectroscopy, and studies of controlled release of drugs. The hybrid hydrogel, pH‐sensitive, was tested at pH values of 1.2 and 7.4 of buffer solution and at a temperature of 37°C to observe its swelling ratio and drug delivery properties with N‐acetylcysteine as a drug material for controlled release. Furthermore, at pH 7.4, the hybrid hydrogel has an outstanding release ratio of up to about 90% absorption amounts of N‐acetylcysteine after 8 hr. The mechanism of drug release from thin film devices (n = 0.684) is anomalous (non‐Fickian) transport, the value of n lies between 0.43 and 0.85.     

Synthesis of a New PHEMA/PEO Enzymatically Biodegradable Hydrogel

Summary: We report the synthesis of a new enzymatically degradable gel based on PHEMA and PEO crosslinking macromonomer. The crosslinker contains the tripeptide sequence Gly‐Gly‐Leu, which is a substrate for proteases such as subtilisin or chymotrypsin. The crosslinker was obtained by the coupling reaction of succinyl‐glycyl‐glycyl‐leucine with 2‐aminoethyl‐terminated PEO chains ( = 3 400) and subsequent esterification of the hydroxyl endgroup with methacryloyl chloride. It was characterized by SEC and ¹H NMR. Enzymatic cleavage of the crosslinking macromonomer was showed by SEC. The macromonomer was copolymerized with HEMA to yield hydrogel that is stable in a physiological buffer. Enzymatic assay showed that this gel is degraded in the presence of a bacterial protease (subtilisin). The degradation is complete within 50 d at 37 °C. This new gel is a good candidate for drug‐delivery systems where the release can be triggered by the presence of bacterial proteases.

PHEMA crosslinked with MA‐PEG‐SucGGL‐PEO‐MA and its degradation by subtilisin.     

Thermodynamics of Carbon Dioxide Adsorption on the Protonic Zeolite H‐ZSM‐5

Adsorption of carbon dioxide on H‐ZSM‐5 zeolite (Si:Al=11.5:1) was studied by means of variable‐temperature FT‐IR spectroscopy, in the temperature range of 310–365 K. The adsorbed CO₂ molecules interact with the zeolite Brønsted‐acid OH groups bringing about a characteristic red‐shift of the O? H stretching band from 3610 cm^?1 to 3480 cm^?1. Simultaneously, the ν₃ mode of adsorbed CO₂ is observed at 2345 cm^?1. From the variation of integrated intensity of the IR absorption bands at both 3610 and 2345 cm^?1, upon changing temperature (and CO₂ equilibrium pressure), the standard adsorption enthalpy of CO₂ on H‐ZSM‐5 is ΔH⁰=?31.2(±1) kJ mol^?1 and the corresponding entropy change is ΔS⁰=?140(±10) J mol^?1 K^?1. These results are discussed in the context of available data for carbon dioxide adsorption on other protonic, and also alkali‐metal exchanged, zeolites.     

Composites of poly (dimethylsiloxane) and spherically shaped poly (2‐hydroxyethylmethacrylate) particles for biomedical use

Silicone rubbers have shown considerable promise in the biomedical field, but their hydrophobicity leads to serious problems in long‐term implants. In our study, composites of poly (dimethylsiloxane) (PDMS) and spherically shaped poly (2‐hydroxyethylmethacrylate) (PHEMA) microparticles were prepared. Unlike previous silicone hydrogel composites, suspension polymerization was carried out in an aqueous medium to prepare PHEMA particles directly, which avoided the removal of organic phase and give hydrogel particles with high purity. Very fine PHEMA particles with uniform geometry and small size were obtained through various influencing factors during their formation. Through the introduction of PHEMA particles, PDMS matrix was endowed with hydrophilicity to a certain extent. With an increase in hydrogel content, higher swelling ability and surface wettability of the composites were observed. We have also demonstrated that smaller sized particles are more favorable for hydrophilicity improvement. The results of improved swelling ability, surface wettability, and low affinity to lipid show that this composite material is suitable for biomedical use. Copyright © 2009 John Wiley & Sons, Ltd.     

Bioelectrocatalysis by Microperoxidase‐11 in a Multilayer Architecture of Chitosan Embedded Gold Nanoparticles

We report on the redox behaviour of the microperoxidase‐11 (MP‐11) which has been electrostatically immobilized in a matrix of chitosan‐embedded gold nanoparticles on the surface of a glassy carbon electrode. MP‐11 contains a covalently bound heme c as the redox active group that exchanges electrons with the electrode via the gold nanoparticles. Electroactive surface concentration of MP‐11 at high scan rate is between 350±50 pmol cm^?2, which reflects a multilayer process. The formal potential (E°′) of MP‐11 in the gold nanoparticles‐chitosan film was estimated to be ?(267.7±2.9) mV at pH 7.0. The heterogeneous electron transfer rate constant (k_s) starts at 1.21 s^?1 and levels off at 6.45 s^?1 in the scan rate range from 0.1 to 2.0 V s^?1. Oxidation and reduction of MP‐11 by hydrogen peroxide and superoxide, respectively have been coupled to the direct electron transfer of MP‐11.     

High performance polymer field‐effect transistors based on polythiophene derivative with conjugated side chain

Poly(3‐[2‐(5‐hexyl‐2‐thienyl) ethenyl]‐2,2′‐bithiophene) ( P2 , see Scheme 1 ) with conjugated thienylvinyl side chain was synthesized by copolymerization of the thiophene units with and without conjugated side chain with Pd‐catalyzed Stille coupling method. For comparison, P1 with the hexyl side chain instead of conjugated side chain was also synthesized. P2 film shows broad absorption in the visible region with absorption edge at about 700 nm. The solution‐processed polymer field‐effect transistors were fabricated and characterized with bottom gate/top contact geometry. The organic field‐effect transistors (OFET) based on P2 showed an average hole mobility of about 0.034 cm²/Vs (the highest value reached 0.061 cm²/Vs) upon annealing at about 180 °C for 30 min, with a threshold voltage of ?1.15 V and an on/off ratio of 10⁴ with n‐octadecyltrichlorosilane (OTS) modified SiO₂ substrate. In comparison, the OFET based on P1 displayed a hole mobility of 8.9 × 10^–4 cm²/Vs and an on/off ratio of 10⁴ with OTS modified SiO₂ substrate. The results indicate that the polythiophene derivative with conjugated thienylvinyl side chain is a promising polymer for the application in polymer field‐effect transistors. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5304–5312, 2009