Glycol Moieties Research Articles

Peginterferon-α-2a (40 kD)

Peginterferon-alpha-2a (40 kD) [Pegasys] comprises an inert, branched, 40 kD polyethylene glycol (PEG) moiety attached to interferon-alpha-2a. Subcutaneous peginterferon-alpha-2a (40 kD) is indicated for the treatment of adults with hepatitis B e antigen (HBeAg)-positive or -negative chronic hepatitis B who have compensated liver disease with evidence of viral replication and hepatic inflammation. Subcutaneous peginterferon-alpha-2a (40 kD) has antiviral and immunomodulatory properties and a convenient once-weekly administration schedule. Forty-eight weeks of therapy with peginterferon-alpha-2a (40 kD) with or without lamivudine was more effective than lamivudine alone in achieving a sustained response in patients with HBeAg-positive or -negative chronic hepatitis B. A long-term follow-up study in patients with HBeAg-positive disease who received peginterferon-alpha-2a (40 kD) monotherapy revealed an HBeAg seroconversion rate of 42%, 1 year after the end of treatment. A long-term follow-up study in patients with HBeAg-negative disease who received peginterferon-alpha-2a (40 kD) with or without lamivudine revealed hepatitis B surface antigen (HBsAg) clearance in 12% of patients and inactive chronic hepatitis B in 17% of patients, 5 years after the end of treatment. Various predictors of response may be useful in terms of identifying patients who may be candidates for shorter or longer peginterferon-alpha-2a (40 kD) treatment durations. For example, quantifying serum HBeAg (in HBeAg-positive disease) and HBsAg levels during therapy may be useful. Adverse events typical of the influenza-like symptoms seen with alpha-interferons occurred more frequently in patients with chronic hepatitis B receiving peginterferon-alpha-2a (40 kD) with or without lamivudine than in those receiving lamivudine alone. In conclusion, peginterferon-alpha-2a (40 kD) is a valuable option for the first-line treatment of HBeAg-negative or -positive chronic hepatitis B.

Cardioprotective activity of a novel and potent competitive inhibitor of lactate dehydrogenase

Alkaline incubation of NADH results in the formation of a very potent inhibitor of lactate dehydrogenase. High resolution mass spectroscopy along with NMR characterization clearly showed that the inhibitor is derived from attachment of a glycolic acid moiety to the 4-position of the dihydronicotinamide ring of NADH. The very potent inhibitor is competitive with respect to NADH. The inhibitor added in submicromolar concentrations to cardiomyocytes protects them from damage caused by hypoxia/reoxygenation stress. In isolated mouse hearts, addition of the inhibitor results in a substantial reduction of myocardial infarct size caused by global ischemia/reperfusion injury.

Hemoglobin-based Oxygen Carriers

Hemoglobin-based Oxygen Carriers

Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors

Prostate cancer cells expressing prostate-specific membrane antigen (PSMA) have been targeted with RNA aptamer-small interfering (si)RNA chimeras, but therapeutic efficacy in vivo was demonstrated only with intratumoral injection. Clinical translation of this approach will require chimeras that are effective when administered systemically and are amenable to chemical synthesis. To these ends, we enhanced the silencing activity and specificity of aptamer-siRNA chimeras by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery. These included adding 2-nucleotide 3'-overhangs and optimizing the thermodynamic profile and structure of the duplex to favor processing of the siRNA guide strand. We also truncated the aptamer portion of the chimeras to facilitate large-scale chemical synthesis. The optimized chimeras resulted in pronounced regression of PSMA-expressing tumors in athymic mice after systemic administration. Anti-tumor activity was further enhanced by appending a polyethylene glycol moiety, which increased the chimeras' circulating half-life.

Hematide™ for the treatment of chronic kidney disease-related anemia

Hematide™ is an investigational erythropoiesis-stimulating agent (ESA) being evaluated for the treatment of anemia in chronic kidney disease patients. It is a dimeric peptide conjugated to a polymeric polyethylene glycol moiety with a sequence completely unrelated to erythropoietin (EPO). Despite this, it is capable of binding to the EPO receptor and promote erythropoiesis through the pathway common to EPO and other ESAs. The drug is partially cleared by the kidney; consequently, its half-life is much longer in the presence of renal insufficiency. Phase III clinical development is ongoing. Preliminary data indicate efficacy of the drug administered once a month either subcutaneously or intravenously. To date, the safety profile appears consistent with that of other ESAs. Even if antibodies against Hematide develop during treatment in some patients, they do not cross-react with EPO. No cases of pure red cell aplasia have been described to date.

Monocomponent hexa- and dodecaethylene glycol succinyl-tocopherol esters: Self-assembly structures, cellular uptake and sensitivity to enzyme hydrolysis

We have chemically synthesized two water-soluble forms of tocopherol succinate linked via an ester bond to hexaethylene glycol and dodecaethylene glycol. The self-assembly structure of the former in water is vesicular, whereas the latter forms elongated micelles. We treated Caco-2 cells with these compounds in these physical forms, in addition to a mixed micelle form. The intact compounds were taken up into the cells, influenced by both the chain length and the physical structure. In addition, the tocopherol derivatives were also metabolized into tocopherol succinate and tocopherol inside the cell. The total hydrolysis and uptake into the cells was two-fold higher from tocopherol hexaethylene glycol succinate in the form of mixed micelles than in vesicular form as assessed by analyzing intracellular tocopherol and tocopherol succinate. The longer polyethylene glycol chain gave a higher intracellular tocopherol succinate/tocopherol ratio. The major intracellular esterase in Caco-2 cells is carboxyl esterase 1 (EC 3.1.1.1), and in silico modelling studies show that the position of docking and hence the site of hydrolysis is influenced by the chain length. The in silico prediction is consistent with the in vitro data, since a longer chain length is predicted to favour hydrolysis of the ester bond between the succinate and polyethylene glycol moieties.

Formulation and characterization of polyphenol-loaded lipid nanocapsules

The purpose of this study was to design and characterize two flavonoid-loaded lipid nanocapsules (LNC) by applying the phase inversion process, and to enhance their apparent solubility and/or the stability. The flavonoid-loaded LNC were characterized by particle size, encapsulation efficiency, drug leakage rates, stability and spectroscopic studies. It was observed that quercetin-loaded LNC30 (3%) and LNC60 (2%) carried a particle size of 30.3 and 55.1 nm, respectively and significant higher entrapment efficiency. Encapsulation of quercetin (QC) in LNC enabled us to increase its apparent aqueous solubility by a factor of 100. And in view of calculations and results, it seems most probable that QC is arranged at this LNC interface between the oil phase and the hydrophilic polyethylene glycol moieties of the surfactant. In addition, colloidal suspensions proved to be stable in term of encapsulation for at least 10 weeks and QC was not oxidised. With simple chemical modification of (−)-epigallocatechin-3-gallate or (−)-EGCG, it was possible to reach very high encapsulation rates (95%). Thus we obtained stable colloidal suspensions of (−)-EGCG in water over 4 weeks while free (−)-EGCG solubilised in water exhibited 100% degradation within 4 h. The initial problems (solubility and stability) of these flavonoids were resolved thanks to drug-loaded LNC.

Synthesis of a novel imidazolium-based electrolytes and application for dye-sensitized solar cells

A series of new imidazolium-based oligomers with different length of a poly(ethylene glycol) moiety as a linker were synthesized and studied as electrolytes for dye-sensitized solar cell (DSSC). These oligomeric molecules are expected to have an intra- or inter-molecular hydrogen bonding interaction through its urethane and urea bonds. They can be used to prepare the liquid-type electrolytes for DSSC by dissolving them into conventional solvent system or to develop solvent-free electrolytes by incorporating an extra redox mediator and other functional materials together as additives. It was found that these oligomers could replace the cationic component of the conventional electrolytes and became the source of redox species when iodine is added. The photocurrent–voltage characteristics of DSSCs with the electrolytes containing these oligomers demonstrated that they can successfully replace the conventional ionic liquid-type electrolytes such as 1-methyl-3-propyl imidazolium iodide (PMII) in 3-methoxypropionitrile (MPN) if the length of the linker is optimized.

Enzymatic surface modification and functionalization of PET: A water contact angle, FTIR, and fluorescence spectroscopy study

The purpose of this study was to investigate the changes induced by a lypolytic enzyme on the surface properties of polyethylene terephthalate (PET). Changes in surface hydrophilicity were monitored by means of water contact angle (WCA) measurements. Fourier Transform Infrared spectroscopy (FTIR) in the Attenuated Total Reflectance mode (ATR) was used to investigate the structural and conformational changes of the ethylene glycol and benzene moieties of PET. Amorphous and crystalline PET membranes were used as substrate. The lipolytic enzyme displayed higher hydrolytic activity towards the amorphous PET substrate, as demonstrated by the decrease of the WCA values. Minor changes were observed on the crystalline PET membrane. The effect of enzyme adhesion was addressed by applying a protease after-treatment which was able to remove the residual enzyme protein adhering to the surface of PET, as demonstrated by the behavior of WCA values. Significant spectral changes were observed by FTIR-ATR analysis in the spectral regions characteristic of the crystalline and amorphous PET domains. The intensity of the crystalline marker bands increased while that of the amorphous ones decreased. Accordingly, the crystallinity indexes calculated as band intensity ratios (1,341/1,410 cm(-1) and 1,120/1,100 cm(-1)) increased. Finally, the free carboxyl groups formed at the surface of PET by enzyme hydrolysis were esterified with a fluorescent alkyl bromide, 2-(bromomethyl)naphthalene (BrNP). WCA measurements confirmed that the reaction proceeded effectively. The fluorescence results indicate that the enzymatically treated PET films are more reactive towards BrNP. FTIR analysis showed that the surface of BrNP-modified PET acquired a more crystalline character.

Pegfilgrastim for PBSC mobilization and autologous haematopoietic SCT

To date, G-CSF is the most favoured cytokine administered for PBSC mobilization because of its great efficacy and lack of serious toxicity. Recently, a pegylated filgrastim (pegfilgrastim) has been introduced. Attachment of the polyethylene glycol (PEG) moiety reduces renal excretion and masks proteolytic cleavage sites resulting in elevated G-CSF serum levels for up to 14 days after a single injection. As single-dose pegfilgrastim had similar effects in the prophylaxis of chemotherapy-induced neutropenia as the daily administration of the unconjugated drug, its capability for the mobilization of haematopoietic stem and progenitor cells has been assessed and presented to be at least equal to that of conventional G-CSF. Administration of pegfilgrastim following high-dose therapy and autologous blood SCT (BSCT) shortened the time to myeloid recovery as seen in conventional G-CSF. Plasma G-CSF levels were about 1 log higher with pegfilgrastim, but in the setting of autologous BSCT this did not translate into a faster haematopoietic recovery. Only few data exist on the biological effects of pegfilgrastim. Still, these data suggest that pegfilgrastim-stimulation results in different functional properties of haematopoietic stem and progenitor cells compared with G-CSF.

Lipeo-sCT: A novel reversible lipidized salmon calcitonin derivative, its biophysical properties and hypocalcemic activity

We have previously described the design and synthesis of Mal-sCT and compared its biological activity with its reversible counterpart, REAL-sCT. Mal-sCT was salmon calcitonin (sCT) conjugated with two molecules of an ɛ-maleimido lysine derivative of palmitic acid via non-reversible thioether bonds at its cysteine residues while REAL-sCT was sCT conjugated with two molecules of a cysteine derivative of palmitic acid via reducible disulfide bonds at its cysteine residues. Neither compounds when dissolved in water could reproducibly improved the oral deliverability of sCT. The purpose of this study was to characterize and evaluate Lipeo-sCT, a novel sCT analog conjugated via reducible disulfide bonds with two amphiphilic groups consisting of a hydrophobic hexadecyl moiety attached via an ether bond to a hydrophilic triethylene glycol moiety. Lipeo-sCT was successfully synthesized by a 4-step reaction, purified and identified by ESI–MS. Analysis by dynamic light scattering (DLS) and transmission electron microscopy (TEM) suggested it had a propensity to form aggregates in water, although the aggregation behavior was controllable by modulating solvent polarity. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay indicated a lack of cytotoxicity against the Caco-2 cells at up to 100 μM. Compared with sCT, Lipeo-sCT lowered plasma calcium to comparable levels when injected subcutaneously at 0.15 mg/kg into female Wistar rats, but the hypocalcemic activity of Lipeo-sCT was prolonged by at least 6 more hours. This was attributable to a continual regeneration of sCT from Lipeo-sCT. sCT was detectable in plasma 8 h following subcutaneous injection of Lipeo-sCT (1.90 mg/kg), while Lipeo-sCT was not observed in plasma at all time points. By comparison, sCT was detectable in plasma for less than 2.5 h following subcutaneous injection at an equivalent dose (1.50 mg/kg). Data from this study complement those of previous studies, and add to the body of knowledge correlating the in vivo activity of lipidized peptides to their physical properties.

Stabilized Integrin-Targeting Ternary LPD (Lipopolyplex) Vectors for Gene Delivery Designed To Disassemble Within the Target Cell

Recent research in the field of nonviral gene delivery vectors has focused on preparing nanoparticles that are stabilized by the incorporation of a PEG coating and where one of the vector components is also cleavable. Here,we describe the synthesis, formulation, transfection properties, and biophysical studies of a PEG-stabilized ternary lipopolyplex vector in which, for the first time, both the lipid and peptide components are designed to be cleaved once the vector has been internalized. A series of cationic lipids, bearing short tri- or hexaethylene glycol groups, attached to the headgroup via an ester linkage, has been prepared. Trifunctional peptides have also been prepared, consisting of a Lys(16) sequence at the N-terminus (to bind and condense plasmid DNA); a spacer group (containing a sequence recognized and cleaved by endosomal enzymes) and an optional PEG4 amino acid; and an integrin-targeting cyclic peptide sequence (allowing the resulting nanoparticle to be internalized via receptor-mediated endocytosis). Differing combinations of these lipids and peptides have been formulated with DOPE and with plasmid DNA, and complex stability, transfection, and cleavage studies carried out. It was shown that optimal transfection activities in a range of cell types and complex stabilities were achieved with lipids bearing short cleavable triethylene glycol moieties, whereas the incorporation of PEG4 amino acids into the cleavable peptides had little effect. We have synthesized appropriate fluorescently labeled components and have studied the uptake of the vector, endosomal escape, peptide cleavage, and plasmid transport to the nucleus in breast cancer cells using confocal microscopy. We have also studied the morphology of these compact, stabilized vectors using cryo-EM.

Synthesis of the starfish ganglioside LLG-3 tetrasaccharide

The first synthesis of the ganglioside LLG-3 tetrasaccharide, which has attractive biological activities as well as a unique structure, is described. A C8-methoxy decorated sialic acid building block was initially prepared and a glycolic acid moiety was then introduced by sialylation. Amide condensation between the sialyl glycolic acid and an amino group at C5 on the sialyllactoside unit afforded the fully protected LLG-3 tetrasaccharide. Finally, the desired tetrasaccharide part of LLG-3 was obtained after careful global deprotection. ▪

ChemInform Abstract: Triarylphosphanes with Dendritically Arranged Tetraethylene Glycol Moieties at the Periphery: An Efficient Ligand for the Palladium‐Catalyzed Suzuki—Miyaura Coupling Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Spotlight on Peginterferon-α-2a (40 kD) Plus Ribavirin in the Management of Chronic Hepatitis C Mono-Infection†

Peginterferon-alpha-2a (40 kD) [Pegasys(R)] is a conjugate of recombinant interferon-alpha-2a and a 40 kD branched polyethylene glycol (PEG) moiety that is highly active against hepatitis C virus (HCV). Ribavirin (Copegus) is a synthetic nucleoside analog that acts in synergy with the antiviral activity of peginterferon-alpha-2a (40 kD). The combination of subcutaneous peginterferon-alpha-2a (40 kD) once weekly plus oral ribavirin twice daily is widely approved for use in adult patients with chronic hepatitis C, including those with persistently 'normal' ALT activity or HIV-HCV co-infection, and is recommended as a first-line treatment option for patients with chronic hepatitis C and compensated liver disease. In randomized, phase III trials, the combination has consistently demonstrated good therapeutic efficacy (i.e. high sustained virologic response [SVR] rates) and has been generally well tolerated in both treatment-naïve and treatment-experienced patients with chronic hepatitis C, including those with compensated, advanced liver disease. Several baseline and dynamic (on-treatment) predictors of an SVR that can be used to guide and optimize therapy were also determined in these trials and in subsequent analyses. By utilizing these predictors, therapy with peginterferon-alpha-2a (40 kD) plus ribavirin can be individualized to achieve the optimal balance between efficacy and tolerability, further increasing the usefulness of this drug combination. Thus, peginterferon-alpha-2a (40 kD) plus ribavirin remains a valuable therapy in patients with chronic hepatitis C, as a first-line option in those with compensated liver disease and as a second-line therapy in those with advanced liver disease.

Water soluble SERS labels comprising a SAM with dual spacers for controlled bioconjugation

Self-assembled monolayers (SAMs) of Raman reporter molecules adsorbed to the surface of metal nanoparticles are labelling agents for the selective detection of biomolecules by surface-enhanced Raman scattering (SERS). Advantages of SAM-based SERS labels include maximum coverage with Raman reporter molecules combined with their uniform molecular orientation within the SAM as well as minimal co-adsorption of other molecules from the surrounding. Water solubility and stability together with the option for controlled bioconjugation are desired properties of SERS labels. We present an approach to synthesize hydrophilic SERS labels in which the colloidal particle is stabilized by two different ethylene glycols attached to the SAM. This guarantees water solubility, independent of the type of a particular Raman reporter molecule and its properties at the SAM/solvent interface. Our dual SAM design is based on two different ethylene glycol spacers covalently bound to the same type of reporter molecule: a short monoethylene glycol (MEG-OH) and a longer triethylene glycol (TEG-COOH) moiety. The terminal carboxy group of the TEG spacer allows subsequent conjugation to biomolecules such as antibodies. Controlled bioconjugation is possible by varying the stoichiometric ratio of both spacers. Finally, dual SAM SERS labels are used in immuno-SERS microscopy for selective imaging of prostate-specific antigen in the epithelium of biopsies from patients with prostate cancer.

Effect of Linker Structure on Surface Density of Aptamer Monolayers and Their Corresponding Protein Binding Efficiency

A systematic study is reported on the effect of linker size and its chemical composition toward ligand binding to a surface-immobilized aptamer, measured using surface plasmon resonance. The results, using thrombin as the model system, showed that as the number of thymidine (T) units in the linker increases from 0 to 20 in four separate increments (T(0), T(5), T(10), T(20)), the surface density of the aptamer decreased linearly from approximately 25 to 12 pmol x cm(-2). The decrease in aptamer surface density occurred due to the increased size of the linker molecules. In addition, thrombin binding capacity was shown to increase as the linker length increased from 0 to 5 thymidine nucleotides and then decreased as the number of thymidine residues increased to 20 due to a balance between two different effects. The initial increase was due to increased access of thrombin to the aptamer as the aptamer was moved away from the surface. For linkers greater in length than T(5), the overall decrease in binding capacity was primarily due to a decrease in the surface density. Incorporation of a hexa(ethylene glycol) moiety into the linker did not affect the surface density but increased the amount of thrombin bound. In addition, the attachment of the linker at the 3'- versus the 5'-end of the aptamer resulted in increased aptamer surface density. However, monolayers formed with equal surface densities showed similar amounts of thrombin binding irrespective of the point of attachment.

Synthesis of tyrosinase inhibitory (4-oxo-4 H-pyran-2-yl)acrylic acid ester derivatives

Melanogenesis is a physiological process that results in the production of melanin pigment. However, excessive accumulations of epidermal pigmentation can cause various hyperpigmentary disorders such as, melasma and age spots. Kojic acid and hydroxylated cinnamic acid derivatives are known to inhibit tyrosinase, a key component of melanin biosynthesis. Pyronyl-acrylic acid esters 3a– i, which share structural features of kojic acid and hydroxylated cinnamic acid, were prepared and their abilities to inhibit tyrosinase and melanin production were evaluated. Of the esters synthesized, 3e and 3h, which derived from diethylene glycol moieties were found to inhibit melanin production by ca. 20% at 20 μg/ml, whereas kojic acid at 200 μg/ml inhibited melanin production by 15.8%.

Triarylphosphanes with Dendritically Arranged Tetraethylene Glycol Moieties at the Periphery: An Efficient Ligand for the Palladium-Catalyzed Suzuki-Miyaura Coupling Reaction

Triarylphosphanes with Dendritically Arranged Tetraethylene Glycol Moieties at the Periphery: An Efficient Ligand for the Palladium-Catalyzed Suzuki-Miyaura Coupling Reaction

Triarylphosphanes with Dendritically Arranged Tetraethylene Glycol Moieties at the Periphery: An Efficient Ligand for the Palladium‐Catalyzed Suzuki–Miyaura Coupling Reaction

Triarylphosphanes with Dendritically Arranged Tetraethylene Glycol Moieties at the Periphery: An Efficient Ligand for the Palladium‐Catalyzed Suzuki–Miyaura Coupling Reaction