Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A method to increase the amount and improve the bioactivity of heparin (HEP) immobilized on a polymer surface was developed. The surface of polyurethane-urea (PU) coated glass beads was first modified with diisocyanates, followed by surface grafting of polyfunctional polymers (PFP), including: poly(vinyl alcohol), poly(ethyleneimine), and poly(allylamine). The functional groups of the surface grafted PFP (-OH, -NH, or -NH2) were modified with diisocyanates (TDI) to amplify the surface concentration of isocyanate groups, alpha, omega-diamino-terminated polyethylene oxide (PEO; molecular weight, 4,000 daltons) was then coupled to the surface grafted PFP, and the free amino groups were derivatized with TDI. Finally, HEP was coupled to the amplified surface through free -NCO groups of PU-PFP-PEO. The surfaces were quantified during each step of the procedures for -NCO groups and HEP. All grafted surfaces showed a four to eightfold increase in -NCO content and a twofold increase in immobilized HEP content compared with HEP immobilized directly onto the PU surface. The HEP bioactivity tests (including activated partial thromboplastin time, thrombin times, and factor Xa) demonstrated an increased bioactivity of HEP when immobilized through PFP-PEO compared with PFP and PU alone.
...
PMID:Heparin immobilization by surface amplification. 145 39

Two polyether-polyurethane elastomers (Pellethane and Biomer) and polyethylene were coated with a heparin-poly(vinyl alcohol) hydrogel. The requisite surface modification in preparation for coating consisted of glow discharge cleaning and acid treatment for the polyether-polyurethanes and glow discharge cleaning and chromic acid oxidation for polyethylene. The chemical modifications increased surface wettability. Surface analysis by attenuated total reflectance Fourier transform infrared spectroscopy indicated that the acid treatment caused hydrolysis of the polyether segments of Pellethane and Biomer. Prolonged partial thromboplastin times were observed on the coated films. The results of toluidine blue assay of heparin in the solution in which the coated films were immersed for a long time suggested that heparin was covalently bound in the coating. Such coating techniques extend the usefulness of the heparin-poly(vinyl alcohol) hydrogel to a number of medically important substrate materials.
...
PMID:Coating of two polyether-polyurethanes and polyethylene with a heparin-poly-(vinyl alcohol) hydrogel. 371 39

Biological effects of the modification of the sulphate ester and carboxyl group content of poly(vinyl alcohol-acrylic acid) copolymers (PAVAS) and sulphated polyvinyl alcohol copolymers (PVAS) with mol. weight of 5,000 to 20,000 D were studied. The in vitro anticoagulant potency of PAVAS assessed by activated partial thromboplastin time (APTT) increased with increasing the overall anionic charge, while differences in mol. weight yielded few obvious effect. The degree of sulphation played an essential part, but the carboxyl group content also contributed to the in vitro anticoagulant activity of PAVAS. On i.v. administration to rats (40 mg/kg), the anticoagulant potency of PAVAS was found to be comparable to that observed in vitro. The ability of PAVAS to induce a state of leukocytosis and decrease serum triglyceride level in rats was also dependent on charge density, and both these effects were increased with elevation of charged groups content irrespectively of mol. weight. Sulphated polyvinyl alcohol copolymers (PVAS) showed similarity to PAVAS charge-dependent biological activities.
...
PMID:Blood coagulation is inhibited by sulphated copolymers of vinyl alcohol and acrylic acid under in vitro as well as in vivo conditions. 808 40

Oligosaccharides of heparin with high affinity for antithrombin III (ATIII) have been immobilized onto surface-modified NHLBI Primary Reference low density polyethylene (PE). PE was modified by radiofrequency plasma polymerized (< 150 nm thick) films derived from N-vinyl-2-pyrrolidone (PPNVP) or allyl alcohol (PPAA), and coupled by chemical derivatization to either 3-aminopropyltriethoxysilane or amino-terminated poly(ethylene oxide). High affinity heparin oligosaccharides (HA-heparin, anti-factor Xa activity of 592 +/- 120 IU/mg) prepared by partial deaminative cleavage of commercial crude heparin and fractionated by agarose-ATIII affinity chromatography, were immobilized to surface-modified PE by reductive amination. The anticoagulant activity, as determined by a chromogenic assay for the inhibition of factor Xa, was estimated to be 30-70 mIU/cm2, with binding estimated to be 56-119 ng/cm2. The highest activity was obtained for the HA-heparin immobilized to PE modified by PPNVP with a PEO spacer. Visual confirmation of ATIII binding to immobilized HA-heparin was demonstrated by a gold-labeled double antibody method with imaging by SEM.
...
PMID:Immobilization of high-affinity heparin oligosaccharides to radiofrequency plasma-modified polyethylene. 840 11

Heparin oligosaccharides with different anticoagulant activities were prepared and immobilized onto pyrolytic carbon coated graphite (PC) heart valve materials commonly used in mechanical heart valve prostheses. Prior to immobilization, PC surfaces were modified by radiofrequency plasma polymerized N-vinyl-2-pyrrolidone (PPNVP) thin films (approximately 100 nm) and derivatized to provide surface hydroxyl groups. Cleaved, low affinity heparin (C-heparin) with factor Xa inhibition activity of 107 to 130 IU/mg, was prepared by partial deaminative cleavage of commercial crude heparin, and high-affinity heparin (HA-heparin) with factor Xa inhibition activity of 550 to 1000 IU/mg was prepared by fractionation of C-heparin using agarose-ATIII affinity chromatography. C-heparin and HA-heparin were immobilized to surface modified PC by reductive amination. Anticoagulant activity of the heparin immobilized surfaces was determined by chromogenic assay for the inhibition of factor Xa. Highest surface anticoagulant activity was measured on C-heparin immobilized surfaces (64.0 +/- 7.3 mIU/cm2) compared with HA-heparin immobilized surfaces (27.2 +/- 12.2 mIU/cm2), suggesting higher binding of C-heparin than HA-heparin on the modified PC surfaces. Immobilized surfaces were evaluated under dynamic flow conditions, by subjecting samples to shear stress of up to 206 dyn/cm2 in the presence of 5% albumin solution or human plasma. Anticoagulant activity of the immobilized heparin was retained, although reduced, and the modified surfaces showed evidence for protein resistance.
...
PMID:Immobilization of heparin oligosaccharides onto radiofrequency plasma modified pyrolytic carbon-coated graphite. 858 11

Heparin (or hydrolyzed heparin) was covalently attached on the surface of derivatized cellulose triacetate membranes, which were subsequently impregnated with the potassium-selective ionophore valinomycin. The resulting ion-selective electrodes presented near-Nernstian response to potassium and had selectivity coefficients of the same order of magnitude as those of conventional poly-(vinyl chloride)-based electrodes. It was found that the heparin layer does not alter significantly the response characteristics of the electrodes. The biological activity of the immobilized heparin (or hydrolyzed heparin) was measured in terms of its inactivation of blood coagulation factor Xa. It was found that the covalently anchored hydrolyzed heparin was not biologically active, but the immobilized heparin was able to inactivate factor Xa. Therefore, by covalently attaching heparin on the surface of ion-selective electrodes, electrodes with improved blood compatibility characteristics may be prepared.
...
PMID:Effect of surface-attached heparin on the response of potassium-selective electrodes. 865 3

In order to prepare polymer surfaces of vinyl type, provided with long-term haemocompatibility, a commercial ethylene-vinyl alcohol copolymer (EVAL) was covalently heparinized, employing two different bifunctional reagents (adipoil chloride and hexamethylene diisocyanate). The amount and activity of the heparin bonded to the polymer films were evaluated as a function of the concentration of the heparin solutions employed. Also, the influence exerted by the presence of various hydrophilic 'spacing arms' of different molecular weights, either neutral or provided with electrical charge, was investigated. By in vitro measurements of activated partial thromboplastin time it was seen that all the heparinized samples possessed a high degree of haemocompatibility. For the sake of comparison, heparin was also bonded ionically to EVAL functionalized by introduction of quaternary ammonium groups bonded covalently (by adipoil chloride) to the hydroxyl groups of the polymer. It was seen that the covalent immobilization system provides the polymer surfaces with a superior haemocompatibility.
...
PMID:Covalent bonding of heparin to a vinyl copolymer for biomedical applications. 918 53

High-throughput screening of a combinatorial library of diamidophenols yielded lead compounds with the ability to inhibit human factor Xa (fXa) at micromolar concentrations (e.g. compound 4, fXa apparent K(ass) = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showed that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phenyl group of one benzoyl group (A-ring) was substituted in the 4-position with relatively small lipophilic or polarizable groups such as methoxy, vinyl, or chloro and the phenyl group of the other benzoyl group (B-ring) was substituted in the 4-position with larger lipophilic groups such as tert-butyl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide variety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxyl substitution produced slightly higher levels of activity than other substituents when present in combination with favorable B-ring substitution. Methylation of the amide nitrogen atoms was found to greatly decrease activity. Compound 12 is the highest affinity fXa inhibitor in this group of compounds, having fXa apparent K(ass) = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can serve to guide future SAR studies.
...
PMID:1,2-Dibenzamidobenzene inhibitors of human factor Xa. 1071 53

We have used organic synthesis to understand the role of L-iduronic acid conformational flexibility in the activation of antithrombin by heparin. Among known synthetic analogues of the genuine pentasaccharidic sequence representing the antithrombin binding site of heparin, we have selected as a reference compound the methylated anti-factor Xa pentasaccharide 1. As in the genuine original fragment, the single L-iduronic acid moiety of this molecule exists in water solution as an equilibrium between three conformers 1C4, 4C1 and 2S0. We have thus synthesized three analogues of 1, in which the L-iduronic acid unit is locked in one of these three fixed conformations. A covalent two atom bridge between carbon atoms two and five of L-iduronic acid was first introduced to lock the pseudorotational itinerary of the pyranoid ring around the 2S0 form. A key compound to achieve this connection was the D-glucose derivative 5 in which the H-5 hydrogen atom has been replaced by a vinyl group, which is a progenitor of the carboxylic acid. Selective manipulations of this molecule resulted in the 2S0-type pentasaccharide 23. Starting from the D-glucose derivative 28, a covalent two atom bridge was now built up between carbon atoms three and five to lock the L-iduronic acid moiety around the 1C4 chair form conformation, and the 1C4-type pentasaccharide 43 was synthesized. Finally the L-iduronic acid containing disaccharide 58 which, due to the presence of the methoxymethyl substituent at position five adopts a 4C1 conformation, was directly used to synthesize the 4C1-type pentasaccharide 61. The locked pentasaccharide 23 showed about the same activity as the reference compound 1 in an antithrombin-mediated anti-Xa assay, whereas the two pentasaccharides 43 and 61 displayed very low activity. These results clearly establish the critical importance of the 2S0 conformation of L-iduronic acid in the activation of antithrombin by heparin.
...
PMID:Synthesis of conformationally locked L-iduronic acid derivatives: direct evidence for a critical role of the skew-boat 2S0 conformer in the activation of antithrombin by heparin. 1176 51

Microwave heating methods have been combined with the use of solid-supported catalysts to produce small solution-phase libraries of medicinally-relevant compounds. Palladium supported on charcoal (Pd/C) has been used to produce libraries of pyrazole compounds for screening in COX II studies via Suzuki cross coupling reactions, while the same catalyst has been used also to produce styryl-based nAChR compounds using analogous chemistry. Although the reaction substrates are very different (aryl vs. vinyl), this catalyst system provided consistently good and reliable results. The use of a polystyrene-supported Ru catalyst for ring-closing metathesis (RCM) reactions was also evaluated to prepare benzolactam structures for evaluation as factor Xa inhibitors.
...
PMID:Combining the use of solid-supported transition metal catalysis with microwave irradiation in solution-phase parallel library synthesis. 1487 Aug 53


1 2 Next >>

---