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PubMed1994

Thermostabilized chemical derivatives of horseradish peroxidase.

Horseradish peroxidase finds a variety of uses in analysis, immunology, organic synthesis, and biosensors. Although moderately stable, its applicability to biosensors and other fields would be greatly enhanced if it could be made yet more stable. Appropriate chemical modification can substantially stabilize enzymes. Here we describe the use of bis-imidates and of bis-succinimides to modify free amino groups of commercial horseradish peroxidase under mild conditions of pH and temperature. Imidates yielded a marginal stabilization. Some of the succinimide derivatives, however, are much more thermostable than the native enzyme. Apparent half-lives indicate stabilizations of 6- to 23-fold, depending on the bis-succinimide used. These modifications preserve the carbohydrate side chains for subsequent reaction or immobilization.

Biosensing Techniques↗
PubMed1984

Structure-dependent variation in the mutagenic, prophage-inducing and antibacterial activities of 5-nitro-2-furamide derivatives.

A comparative survey of the mutagenic, prophage-inducing and antibacterial activities of 3 structure-related series of 5-nitro-furan derivatives including 5-nitro-2-furohydrazide imide, 5-nitro-2-furamide oxime and 5-nitro-2-furohydrazide has been undertaken. Among the compounds assayed, the 5-nitro-2-furohydrazide imide series was found to be most active with regard to mutagenic and antibacterial activities against Salmonella typhimurium TA100 and prophage-inducing activity in Escherichia coli GY5027. A clear correlation was observed between the chemical structure and the mutagenic and prophage-inducing activities which were approximately correlated to the antibacterial activity.

Anti-Bacterial Agents↗
PubMed1991

The thalidomide analog, EM 12, enhances 1,2-dimethylhydrazine-induction of rat colon adenocarcinomas.

Young male Sprague-Dawley rats in 3 groups were fed a basal diet supplemented with 0.10 wt. % each of thalidomide and its imide-analog of much higher teratogenicity, EM 12. Following an induction period of 17 days on the diets, all animals were injected subcutaneously with 1,2-dimethylhydrazine at 20 mg/kg for a total of 20 weekly doses and killed on week 18 after the 20th injection. The total number of colon adenocarcinomas and their occurrence in the proximal and distal portions for the thalidomide-treated rats were similar to those of the respective controls. However, the EM 12-fed group elicited statistically significant increases both in the total and ascending colon-based adenocarcinomas as compared with the control findings, in keeping with its greater teratogenicity and embryotoxicity. The numbers of small intestinal adenocarcinomas were equally higher in the imide-fed groups in contrast to the control frequency.

1,2-Dimethylhydrazine↗
PubMed1992

Preparation of a chemiluminescent imidoester for the non-radioactive labelling of proteins.

A chemiluminescent aryl acridinium ester was synthesized which possesses an imidate ester group capable of reacting with proteins under mild conditions. The compound can be detected at levels as low as 5.2 x 10(-19) mol using commercially available luminometers and can therefore be used to produce high specific activity labelled antibodies for use in immunochemiluminometric assays. The imidate ester compares favourably with a previously reported N-succinimidyl ester in terms of its labelling properties but is easier to synthesize, requiring one less step. The compound was used to label affinity purified to synthesize, requiring one less step. The compound was used to label affinity purified sheep antibodies to human parathyroid hormone to demonstrate its utility in a two-site immunochemiluminometric assay for the measurement of intact parathyroid hormone.

Acridines↗
PubMed2005

Bioelectrocatalysis in ionic liquids. Examining specific cation and anion effects on electrode-immobilized cytochrome c.

Cytochrome c immobilized on alkylthiol self-assembled monolayers exhibits a characteristic Fe(II)/Fe(III) redox signal that is lost when exposed to ionic liquids composed of a butylimidazolium cation combined with either hexafluorophosphate or bis(trifluoromethylsulfonyl)imide anion. In this study it was shown that exposure to the aqueous solubilized ionic liquid components, butyl-, hexyl-, and octyl-imidazolium cations and hexafluorophosphate, tetrafluoroborate, and bis(trifluoromethylsulfonyl)imide anions, resulted in partial electrochemical signal loss. Absorbance and fluorescence measurements showed that signal loss due to the cationic ionic liquid component followed a different mechanism than that of the anionic component. Although a portion of the signal was recoverable, irreversible signal loss also occurred in both cases. The source of the irreversible component is suggested to be the loss of protein secondary structure through complexation between the ionic liquid components and the protein surface residues. The reversible electrochemical signal loss is likely due to interfacial interactions imposed between the electrode and the cytochrome heme group. The influence of the amount of exposed surface residues was explored with a simplified model protein, microperoxidase-11.

Anions↗
PubMed2005

Polyelectrolyte complex formation and stability when mixing polyanions and polycations in salted media: a model study related to the case of body fluids.

Controlled drug delivery and gene transfection involve contact of artificial polyelectrolytic systems that can interact dramatically with biopolymers and cells when they are introduced in blood. Given the complexity of body aqueous media in terms of physical chemistry, a model approach was selected in attempt to understand the behavior of artificial polyelectrolytes introduced in body fluids. Selection in terms of molecular weight was highlighted in a previous paper. In the present study the formation and the stability of fractions obtained when a polycation is added to a polyanion according to a titrating process mimicking injection into blood was considered for different polycation/polyanion couples. Poly(amino serinate) and poly(L-lysine) were used as polybases, and poly(acrylic acid), poly(L-lysine citramide) and poly(L-lysine citramide imide) as polyacids. Four fractions corresponding to different positive/negative charge ratios were formed for each couple. At low polyion concentration (13 mg/L) and given salt concentration, the stability of the complex fractions depended on molecular weight and charge density of the polyions. The NaCl concentration required to destabilize the different interpolyelectrolyte complexes was found to decrease from the first fraction to the fourth one. Upon decreasing the salt concentration, macroscopic flocculation occurred in the case of PLL/PAA complex fractions only. For the other couples, dynamic light scattering showed that several hundreds nanometer sized particles were formed that were stable in a broad range of NaCl concentration, including the physiological 0.15 ionic strength. At higher polyion concentrations, stable solid precipitate was formed regardless of the system. The absence of flocculation in the case of highly diluted poly(L-lysine citramide) and poly(L-lysine citramide imide) polyanions in salted media is assigned to the presence of non-ionic hydroxyl and amide polar groups along the complexed chains. Data show that introducing non-ionic functions along the polyelectrolyte chains is a good means to keep interpolyelectrolyte complexes dispersed in salted media, a conclusion of interest in the field of condensation of genes by polycations.

Body Fluids↗
PubMed2005

Changes in left atrial size in patients with persistent atrial fibrillation: a prospective echocardiographic study with a 5-year follow-up period.

Atrial fibrillation (AF) is a common arrhythmia, occurring in 0.4% of the general population. AF has been shown to be associated with left atrial enlargement, which is considered both a cause and a consequence of the arrhythmia. The aim of the study was to determine the influence of AF on changes in echocardiographically determined left atrial (LA) size, during 5 year follow-up period, in a population with well-controlled hypertension, free from structural heart disease, except mild left ventricle thickening, and with an absence of other potential causes of atrial enlargement. The study group, comprised of 81 patients with persistent AF, with underlying hypertensive heart disease, consecutively referred for elective direct current cardioversion. The mean age of the study population was 59.3+/-8.4 years (ranged from 43 to 80), a mean AF duration was 8.8+/-8.7 months (ranged from 1 to 30 months). The patients underwent two-dimensional echocardiography to determine left atrial size, before and 5 years after cardioversion. Twenty out of eighty-one cardioverted patients maintained sinus rhythm 5 years after cardioversion (25%). In this group anteroposterior LA dimension and LA volume decreased from a mean (+/-S.D.) 49.7+/-4.5 to 46.8+/-4.8 mm (-6%, p < 0.05) and from 103.6+/-28.8 to 91.1+/-18.3 cm2 (-9.2%, p < 0.05), respectively. Left ventricle ejection fraction increased from 52.8+/-6.3% to 60.0+/-4.0% (p < 0.05) and clinical stage improved in patients who maintained sinus rhythm through 5 years. In contrast, in the AF group, anteroposterior LA dimension and LA volume increased from 46.6+/-4.3 to 48.1+/-5.6 mm, and from 91.3+/-20 to 103+/-34 cm2 (by an average 3.3% and 14.3%, respectively), at the end of study. When divided into two groups: Imid R:II and III NYHA class, in AF patients LA volume increased by an 21.4% in the III NYHA class and 7.3% in the Imid R:II NYHA class. Left ventricular ejection fraction did not change between the two echocardiographic studies in the AF group (44.9+/-14.3% vs. 44.6+/-12.9%, Ns). In conclusion, it has been proved that AF occurring in patients with hypertensive heart disease causes a slow and progressive increase in LA size especially in patients in functional III NYHA class, and that the maintenance of sinus rhythm partially reverts the process of LA enlargement in patients with well-controlled hypertension, a history of AF and successfully treated for AF.

Adult↗
PubMed2004

The distribution of the unoccupied volume in glassy polymers.

The aim of this paper is to present an improved method to describe the unoccupied volume in glassy polymers. The method is able to treat atoms with non-spherical symmetry. The fineness of the raster points scanning the unit cell can be as small as 0.01 nm. This method was used to determine the unoccupied volume of molecular dynamic simulations of poly(amide imide) unit cells by probing it with a tracer atom. Since the reachable unoccupied volume strongly depends on the tracer radius, we used tracer radii between 0.03 and 0.17 nm. The poly(amide imide)s were used in the present work because they are well characterized, especially there already exist free volume data determined by positron lifetime experiments.

Computer Simulation↗
PubMed2005

[Thalidomide: mechanisms of action and new insights in hematology].

Purpose. - Thalidomide, a major teratogen drug, was rehabilitated mainly in malignant hemopathy. Current knowledge and key points. - Thalidomide-mechanisms of action are well known, multiple, they combine immunomodulatory, antiangiogenic properties, and the modulation of cytokines, particularly tumour necrosis factor-alpha. Multiple trials are ongoing, however, the main indication remain multiple myeloma with a response rate of 30% in relapsed patients. Future prospects and projects. - New structural analogues of the thalidomide which priviligiate some of the thalidomide-specific mechanisms of action, the selected cytokine inhibitory drugs (SelCIDS) and the immunomodulatory drugs (IMiDs) family are under evaluation. The IMiDs, which mechanism is based on stimulation of T lymphopoiesis rather than inhibition of tumour necrosis factor-alpha, are under clinical trials in multiple myeloma with interesting results.

Amyloidosis↗
PubMed2004

Targeted gene therapy: frontiers in the development of 'smart drugs'.

Chronic diseases, particularly malignancies and immune-mediated inflammatory diseases (IMIDs), are a challenging frontier for clinical diagnosis and treatment, as well as for biomedical research. Current treatment regimens are frequently insufficient and thus new treatment strategies are needed. Novel therapies for disabling such diseases should provide improvements with respect to safety, efficacy and cost. To fulfill these three key criteria, recent research efforts have focused on the development of 'smart drugs'. This review highlights some examples of the rapidly expanding possibilities that current biotechnology has to offer in the development of novel therapeutic strategies for complex diseases such as IMIDs. Special attention is given to advances in, and limitations of, controlled and targeted gene product application in inflammatory diseases.

Antibodies, Monoclonal↗
PubMed1995

On the pH dependence of amide proton exchange rates in proteins.

We have analyzed the pH dependencies of published amide proton exchange rates (kex) in three proteins: bovine pancreatic trypsin inhibitor (BPTI), bull seminal plasma proteinase inhibitor IIA (BUSI IIA), and calbindin D9K. The base-catalyzed exchange rate constants (kOH) of solvent exposed amides in BPTI are lower for residues with low peptide carbonyl exposure, showing that the environment around the carbonyl oxygen influences kOH. We also examined the possible importance of an exchange mechanism that involves formations of imidic acid intermediates along chains of hydrogen-bonded peptides in the three proteins. By invoking this "relayed imidic acid exchange mechanism," which should be essentially acid-catalyzed, we can explain the surprisingly high pHmin (the pH value at which kex reaches a minimum) found for the non-hydrogen-bonded amide protons in the beta-sheet in BPTI. The successive increase of pHmin along a chain of hydrogen-bonded peptides from the free amide to the free carbonyl, observed in BPTI, can be explained as an increasing contribution of the proposed mechanism in this direction of the chain. For BUSI IIA (pH 4-5) and calbindin D9K (pH 6-7) the majority of amide protons with negative pH dependence of kex are located in chains of hydrogen-bonded peptides; this situation is shown to be consistent with the proposed mechanism.

Amides↗
PubMed2002

Synthesis and antimicrobial activity of new adamantane derivatives III.

Some novel ester imides synthesised from trimellitic acid anhydride and 1-adamantanol or 2-adamantanol, were tested as antimicrobial compounds. Unfortunately, these agents showed a modest antibacterial activity (MIC > 6 microg/ml). However, a comparison of these N-substituted adamantylester imides with the series published previously, indicated that the incorporation of L-alanine and L-phenylalanine into the phthalimide moiety was the best choice regardless of the series and leads to antimicrobial activity against Staphylococcus aureus strains.

Adamantane↗
PubMed2003

Tumor necrosis factor-alpha production-regulating activity of phthalimide derivatives in genetically modified murine melanoma cells B78H1.

The effect of imides, monothioimides, trimellitimides, as well as 5'-deoxy-5'-phthaloylamino-derivatives of azidothymidine on tumor necrosis factor-alpha (TNF-alpha) production by genetically modified murine B78H1 melanoma cells transduced with the gene for human TNF-alpha (B78/TNF) was investigated. It was found that N-(adamant-1-yl)monothiophthalimide (1e) and N-(adamant-2-yl)-monothiophthalimide (1f) showed over 200% enhancing of TNF-alpha production while some of imides were inhibitors.

Animals↗
PubMed1989

High-performance liquid chromatography of amino acids, peptides and proteins. XCI. The influence of temperature on the chromatographic behaviour of peptides related to human growth hormone.

The influence of temperature on the gradient elution properties of synthetic peptides related to residues [6-13] of human growth hormone, e.g., Leu1-Ser-Arg-Leu-Phe-Asp-Asn-Ala8, has been studied by using both an octadecylsilica and a polymeric fluorocarbon stationary phase. Correlation of changes in the solute hydrophobic contact area and affinity for the stationary phase, as given by S and log k0 values respectively, revealed that the alpha- and imide forms are more conformationally stable than the beta-linked peptide. In addition, negative values of the standard entropy change, delta S0 assoc, for the transfer of the solute to the stationary phase, were observed for both alpha- and beta-linked peptides. These results are indicative of an increased ordering of the system upon solute adsorption and implies that the open-chain peptides exist in solution in more flexible conformations, while the helical structure of the cyclised imide is more rigid and constrained. The implications of the relative conformational stability of these peptides in their role as insulin-potentiating agents is also discussed.

Amino Acids↗
PubMed2000

Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors.

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.

Animals↗
PubMed2000

Ligands for the common allosteric site of acetylcholine M2-receptors: development and application.

Ligands for the allosteric site of acetylcholine M2 receptors are able to retard the dissociation of simultaneously bound ligands for the orthosteric site. This effect promotes receptor occupation by the orthosteric ligand. The allosteric effect opens various therapeutic perspectives, e.g., in organophosphorus poisoning. The aim of our studies was to optimize the affinity of the modulators for the common allosteric binding site of muscarinic M2 receptors, the orthosteric site of which was liganded with the N-methylscolopamine. The phthalimido substituted hexane-bisammonium compound W84 served as a starting point. Previous molecular modelling studies revealed two positive charges and two aromatic imides in a sandwich-like arrangement to be essential for a high allosteric potency. A three-dimensional quantitative structure activity relationship (3D QSAR) analysis predicted compounds with substituents of increasing size on the lateral imide moieties to enhance the affinity for the allosteric binding site. Thus, we synthesized and pharmacologically evaluated compounds bearing "saturated" phthalimide moieties as well as phthalimidines with substituents of systematically increasing size in position 3 or on the aromatic ring at one or both ends of the molecule. Within each series, QSAR could be derived: 1. "Saturation" of the aromatic ring of the phthalimide moiety results in less potent compounds. 2. Increasing the size of the substituents in position 3 of the phthalimide enhances the potency. 3. Putting substituents on the aromatic part of the phthalimide increases the potency more effectively: the introduction of a methyl group in position 5 gave a compound with a potency in the nanomolar concentration range which was subsequently developed as the first radioligand for the allosteric binding site.

Animals↗
PubMed2001

Novel therapies targeting the myeloma cell and its bone marrow microenvironment.

Novel therapies in multiple myeloma (MM) target not only the tumor cell but also the bone marrow (BM) microenvironment. Thalidomide (Thal), as well as derivative immunomodulatory drugs (IMiDs), directly induce apoptosis or G1 growth arrest in MM cell lines and patient's MM cells which are resistant to melphalan (Mel), doxorubicin (Dox), and dexamethasone (Dex). Although Thal and IMiDs do not alter adhesion of MM cells to bone marrow stromal cells (BMSCs), they inhibit the upregulation of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion triggered by the binding of MM cells to BMSCs. Proteasome inhibitors represent another potential anticancer therapy targeting the MM cell and the BM microenvironment. The proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis in both human MM cell lines and freshly isolated patient's MM cells which are resistant to Mel, Dox, and Dex. PS-341 inhibits p44/42 mitogen-activated protein kinase (MAPK) growth signaling triggered by IL-6 and induces apoptosis, despite induction of p21 and p27, in p53 wild-type and p53 mutant MM cells. PS-341 adds to the anti-MM activity of dexamethasone and overcomes IL-6-mediated protection against dexamethasone-induced apoptosis. PS-341 blocks the paracrine growth of human MM cells by decreasing their adherence to BMSCs and related NF-kappaB-dependent induction of IL-6 secretion in BMSCs. Moreover, proliferation and MAPK growth signaling of those residual adherent MM cells is also inhibited. Tumor necrosis factor-alpha (TNF-alpha), which is produced by some MM cells, induces only low-level MM proliferation and MAPK activation in MM cells, but markedly upregulates IL-6 secretion from BMSCs and upregulates expression of adhesion molecules (VLA-4 and LFA-1) on MM cells and their receptors (VCAM-1 and ICAM-1) on BMSCs, with resultant increased binding of MM cells to BMSCs. Inhibition of TNF-alpha-induced NF-kappaB activation with PS-341 inhibits both the upregulation of these molecules on MM cells and BMSCs and the resultant increased adhesion. Therefore, inhibiting TNF-alpha and its sequelae may be useful treatment strategies in MM. Our data show that VEGF causes proliferation and enhances migration of MM as well as plasma cell leukemia (PCL) cells. VEGF induced twofold activation of cell migration in MM cells and more than 100-fold activation of cell migration in PCL cells, suggesting an important role of VEGF in the progression of MM to PCL. These data indicate that VEGF plays a pivotal role not only in neoangiogenesis in MM BM but also in proliferation and migration of tumor cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Kinetic data for redox reactions of cytochrome c with Fe(CN)5X complexes and the question of association prior to electron transfer.

Use of rigorous equilibration kinetics to evaluate rate constants for the Fe(CN)6 4- reduction of horse-heart cytochrome c in the oxidized form, cyt c (III), has shown that limiting kinetics do not apply with concentrations of Fe(CN)6 4- (the reactant in excess) in the range 2-10 x 10(-4) M, I = 0.10 M (NaCl). The reaction conforms to a first-order rate law in each reactant, and at 25 degrees C, pH 7.2 (Tris), it is concluded that K for association prior to electron transfer is less than 200 M-1. From previous studies at 25 degrees C, ph 7.0 (10(-1) M phosphate), I = 0.242 M (NaCl), a value K = 2.4 x 10(3) M-1 has been reported. Had such a value applied, some or all of the redox inactive complexes Mo(CN)8 4-, Co(CN)6 3-, Cr(CN)6 3-, Zr(C2O4)4 4- present in amounts 5-20 x 10(-4) M would have been expected to associate at the same site and partially block the redox process. No effect on rats was observed. With the reductants Fe(CN)5(4-NH2-py)3- and Fe(CN)5(imid)3-, reactions proceeded to greater than 90% completion and rate laws were again first order in each reactant. Rate constants (M-1 sec-1) at 25 degrees C, pH 7.2 (Tris), I = 0.10 M (NaCl), are Fe(CN)6 4- (3.5 x 10(4)), Fe(CN)5(4-NH2py)3- (6.7 x 10(5), and Fe(CN)5(imid)3- (4.2 x 10(5). Related reactions in which cyt c(II) is oxidized are also first order in each reactant, Fe(CN)6 3- (9.1 x 10(6)), Fe(CN)5(NCS)3- (1.3 x 10(6)), Fe(CN)5(4-NH2py)2- (3.8 x 10(6) at pH 9.4), and Fe(CN)5(NH3)2- (2.75 x 10(6) at ph 8). Redox inactive Co(CN)6 3- (1.0 x 10(-3) M) has no effect on the reaction of Fe(CN)6 3- which suggests that a recent interpretation for the Fe(CN)6 3- oxidation of cyt c(II), I = 0.07 M, may also require reappraisal.

Animals↗