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At least 721 records · Page 40Linked to original sources
PubMed2003

Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines.

An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 15 is reported. The procedure started by solid supporting a p-hydroxybenzaldehyde 8 to the Wang resin by using the Mitsunobu protocol. The resulting aldehyde 17 was treated with a substituted acid methyl malonate 10 to afford the corresponding alpha, beta-unsaturated ester 18, which was converted to the Michael adduct 21 by reaction with malononitrile. Cyclization of 21 with an amidine system 13 yielded the solid supported pyridopyrimidine 22, which afforded the corresponding 2-substituted 4-aminopyrido[2,3-d]pyrimidine 15 upon treatment with TFA:DCM. Compounds 15 present three diversity centers R1, R2 and R3. Having validated the chemistry on solid support, a 32-membered combinatorial library was obtained using this protocol.

Combinatorial Chemistry Techniques↗
PubMed1991

Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury.

Previous studies in this laboratory have documented tumor necrosis factor alpha (TNF) release by macrophage laden glomeruli in the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN). We now report that the administration of anti-TNF antiserum to rats with the AA-NTSN reduces albuminuria in a dose related manner (day 8 postinduction) and limits glomerular necrosis (P less than 0.05) without affecting the endogenous creatinine clearance (CCr). Protease inhibitors block cytolytic activity of TNF in vitro and reduce glomerular necrosis in experimental nephritis in vivo. The combined administration of anti-TNF antiserum and an amidine-type protease inhibitor (BABIM) to rats with the AA-NTSN caused a greater diminution of albuminuria and histopathology than observed in rats treated with either agent alone, and also prevented the fall in CCr otherwise observed in this model system. Since, in our studies, BABIM did not inhibit cytolytic TNF activity in vitro, we conclude that the effects of combined administration of these two agents are mediated by independent mechanisms. Our results highlight the pathogenic significance of local TNF release in immune renal disease accompanied by prominent glomerular macrophage accumulation.

Albuminuria↗
PubMed2003

Efficient synthesis of 2,9-disubstituted 8-hydroxyadenine derivatives.

An efficient and general method for the synthesis of 2,9-disubstituted 8-hydroxyadenines, which are expected to have various biological activities, was realized. 5-Amino-4-cyano-2-hydroxyimidazoles(1) were prepared from aminomalononitrile and isocyanates as key intermediates. The condensation of 1a with amidines, imidates, guanidine, urea and thioureas afforded 8-hydroxyadenines (2-6) possessing various substituents at the 2-position. Furthermore, selective alkylation of 2-amino- and 2-hydroxyadenines (4 and 6) successively proceeded to give the corresponding 2-alkylamino- and 2-alkoxyadenines (5 and 7), respectively. 2-Alkylthioadenines (15) were prepared by an analogous reaction of 1a with benzoyl isothiocyanate and subsequent S-alkylation. The imidazoles 1 are most useful intermediates for the synthesis of 8-hydroxyadenine derivatives.

Journal Article↗
PubMed2003

Traceless solid phase synthesis of 2-substituted pyrimidines using an 'off-the-shelf' chlorogermane-functionalised resin.

The parallel solid phase synthesis of an 18-member library of 2-substituted pyrimidines is described using a chlorogermane-functionalised resin. The success of the key Pinner-type condensations between a resin-bound enaminone and an array of amidine hydrochlorides highlights the stability of arylgermane linkers (cf. arylsilanes) towards strongly basic/nucleophilic conditions.

Journal Article↗
PubMed2005

Olefination and group transfer reactions of an electron deficient tantalum methylidene complex.

The reactivity of an electronically unsaturated tantalum methylidene complex [TolC(NSiMe(3))(2)](2)Ta(CH(2))CH(3) supported by [TolC(NSiMe(3))(2)] amidinate ligands is described. Electrophilic addition and olefination reactions of the Ta=CH(2) functionality are reported. Alkylidene participates in group-transfer reactions not observed in sterically similar, but electronically saturated, analogues. Reactions with substrates containing unsaturated C-X (X = C, N, O) bonds yield [Ta]=X compounds and vinylated organic products; carbon-sulfur cleavage reactions to produce tantalum thioformaldehyde and tantalum sulfido complexes.

Journal Article↗
PubMed2006

A new family of luminescent compounds: platinum(II) imidoylamidinates exhibiting pH-dependent room temperature luminescence.

The imidoylamidinate platinum(II) compounds [Pt{NH=C(R)NC(Ph)NPh}2] (R = CH2Ph 2, p-ClC6H43, Ph 4) were prepared by the reaction of the appropriate trans-[PtCl2(RCN)2] with 4 equiv of the amidine PhC(NH)NHPh giving 2-4 and 2 equivs of the salt PhC(=NH)NHPh.HCl. We also synthesized, by the double alkylation of 4 with MeOSO2CF3, complex [Pt{NH=C(Ph)N(Me)C(Ph)=NPh}2][CF3SO3]2 (5) which models the bis-protonated form of 4. The complexes were characterized by 1H, 13C NMR, and IR spectroscopies, FAB-MS and by C, H, N elemental analysis. The X-ray crystallography of 4.2CH2Cl2 enables the confirmation of the square planar coordination geometry of the metal center with almost planar imidoylamidine ligands, while in 5.2CHCl3 the planarity of the metallacycles is lost and and the central N atom is sp3-hybridized. The imidoylamidinate complexes represent a new family of Pt(II)-based luminescent complexes and they are emissive at room temperature both in solution and in the solid state, with an emission quantum yield ranging from 3.7 x 10(-4) to 6.2 x 10(-2) in methanol solution; the emission intensity is pH-dependent, being quenched at low pH. UV-visible and luminescence spectroscopies indicate that the lowest excited state of these compounds is 3MLCT or 3IL with significant MLCT character, with emission lifetimes of a few micros. A blue shift of both the absorption and emission with increasing solvent polarity and with decreasing pi-electron withdrawing properties of the ligand substituent was observed.

Journal Article↗
PubMed2007

Synthesis and structures of selected benzamidinates of Li, Na, Al, Zr and Sn(II) using the C1-symmetric ligands [N(SiMe3)C(C6H4Me-4 or Ph)NPh]-.

Several compounds based on the C(1)-symmetric ligands [N(R)C(Ar)NPh]- [abbreviated as B1 (Ar = C(6)H(4)Me-4) or B2 (Ar = Ph), R = SiMe(3)] are reported. They are the crystalline metal benzamidinates [Li(mu:kappa2-B1)(OEt2)](2) (1), [Al(kappa2-B1)2Me] (2), [Al(kappa2-B1)2X] [X = Cl/Me, 1 : 1 (3)], [Sn(kappa2-B1)2] (4), Zr(kappa2-B1)2Cl2 (5), [Zr(kappa2-B1)3Cl] (6), [Na(mu:kappa2-B1)(tmeda)]2 (7), K[B1] (8), Li(B2)(OEt2) (9) and Zr(kappa2-B1)3Cl (10) and the known benzamidine Z-H2NC(C6H4Me-4) = NPh (11). They were prepared by (i) insertion of the nitrile 4-MeC6H4CN (1, 7, 8, 11) or PhCN (9) into the appropriate M-N(R')Ph [R' = R and M = Li (1, 9), Na (7), K (8)] bond and subsequent hydrolysis for 11 [R' = H and M = Li], or (ii) a ligand transfer reaction using the lithium amidinate 1 and Al(Me)2Cl (2, 3), SnCl2 (4) or ZrCl4 (5, 6), or Li(B2) and ZrCl4 (10). The X-ray structures of 1, 2, 3, 4, 6b (i.e..3PhMe) 7, and 11 are presented. Exploratory polymerisation experiments are described, using 2, 5 or 6 as a procatalyst with methylaluminoxane (MAO) (Al : Zr ca. 500 : 1) as promoter. Thus toluene solutions were exposed to C2H4 under ambient conditions; while 2 was unresponsive, 5 and 6 showed modest activity in the formation of polyethylene.

Journal Article↗
PubMed1978

Purification and properties of glutamate synthase and glutamate dehydrogenase from Bacillus megaterium.

Bacillus megaterium N.C.T.C. no. 10342 exhibits glutamate synthetase (EC 2.6.1.53) and glutamate dehydrogenase (EC 1.4.1.4) activities. Concentrations of glutamate synthase were high when the bacteria were grown on 3mM-NH4Cl and low when they were grown on 100mM-NH4Cl, whereas glutamate dehydrogenase concentrations were higher when the bacteria were grown on 100mM-NH4Cl than on 3mM-NH4Cl. Glutamate synthase and glutamate dehydrogenase were purified to homogeneity from B. megaterium grown in 10mM-glucose/10mM-NH4Cl. The purified enzymes had mol.wts. 840000 and 270000 for glutamate synthase and glutamate dehydrogenase respectively. The Km values for substrates with NADPH and coenzyme were (glutamate synthase activity shown first) 9 micron and 360 micron for 2-oxoglutarate, 7.1 micron and 8.7 micron for NADPH, and 0.2 mM for glutamine and 22 mM for NH4Cl, similar values to those of enzymes from Escherichia coli. Glutamate synthase contained NH3-dependent activity (different from authentic glutamate dehydrogenase), which was enhanced 4-fold during treatment at pH 4.6 NH3-dependent activity was generally about 2% of the glutamine-dependent activity. Amidination of glutamate synthase by the bi-functional cross-linking reagent dimethyl suberimidate inactivated glutamine-dependent glutamate synthase activity, but increased NH3-dependent activity. A cross-linked structure of mol.wt. approx 200000 was the main product formed.

Amino Acids↗
PubMed1981

Specific one-stage method for assay of enterokinase activity by release of radiolabelled activation peptides from alpha-N-[3H]acetyl-trypsinogen and the effect of calcium ions on the enzyme activity.

We report a novel assay method for enterokinase capable of detecting approx. 1 fmol of enzyme. The method depends on quantification of the release of specifically radiolabelled activation peptides from bovine trypsinogen and is unaffected by trypsin inhibitors. The assay is applicable to biological fluids such as serum. The substrate was produced by selective epsilon-amidination of bovine trypsinogen followed by acetylation with [3H]acetic anhydride and deprotection. The assay has been used to study the effects of pH, Ca2+, ionic strength abd glycodeoxycholate on enterokinase activity.

Acetylation↗
PubMed2001

Alteration of the specificity of malate dehydrogenase by chemical modulation of an active site arginine.

Malate dehydrogenase from Escherichia coli is highly specific for the oxidation of malate to oxaloacetate. The technique of site-specific modulation has been used to alter the substrate binding site of this enzyme. Introduction of a cysteine in place of the active site binding residue arginine 153 results in a mutant enzyme with diminished catalytic activity, but with K(m) values for malate and oxaloacetate that are surprisingly unaffected. Reaction of this introduced cysteine with a series of amino acid analog reagents leads to the incorporation of a range of functional groups at the active site of malate dehydrogenase. The introduction of a positively charged group such as an amine or an amidine at this position results in improved affinity for several inhibitors over that observed with the native enzyme. However, the recovery of catalytic activity is less dramatic, with less than one third of the native activity achieved with the optimal reagents. These modified enzymes do have altered substrate specificity, with alpha-ketoglutarate and hydroxypyruvate no longer functioning as alternative substrates.

Arginine↗
PubMed2005

Metabolism of benzamidoxime (N-hydroxyamidine) in human hepatocytes and role of UDP-glucuronosyltransferases.

N-Hydroxyamidines (amidoximes) can act as pro-drugs of amidines (e.g. ximelagatran, a novel direct thrombin inhibitor). This known pro-drug principle is based on the N-reduction of an oral bioavailable amidoxime to its active form. Previous study of the metabolism of the model substrate benzamidoxime by pig hepatocytes demonstrated the formation of benzamidoxime-O-glucuronide in addition to the well-established N-reduction. The objective of the present work was to investigate the glucuronidation of benzamidoxime by using cultivated cryopreserved human hepatocytes. Furthermore, the involvement of human UDP-glucuronosyltransferases (UGTs) was examined by incubating benzamidoxime in the presence of eight human hepatic recombinant UGT enzymes. Metabolites were analysed by liquid chromatography/mass spectrometry using electrospray ionization and compared with authentic synthetic compounds. For the first time, the O-glucuronidation of benzamidoxime was demonstrated in cultures of human hepatocytes. UGT1A9 is the most efficient enzyme conjugating benzamidoxime, whereas the conversion activities of UGT1A1 and UGT1A3 were 60-fold lower. Human hepatocytes form two non-mutagenic compounds: benzamidine, as the predominating metabolite, and benzamidoxime-O-glucuronide to a lesser extent. N-oxidation of benzamidine was not detected.

Benzamidines↗
PubMed2005

In vitro metabolism of an orally active O-methyl amidoxime prodrug for the treatment of CNS trypanosomiasis.

A new aza-analogue of furamidine, 6-[5-(4-amidinophenyl)-furan-2-yl]nicotinamidine (DB820), has potent in vitro antitrypanosomal activity; however, it suffers from poor oral activity because of its positively charged amidine groups. The dimethoxyamidine prodrug of DB820, N-methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine (DB844), has potent oral activity in mouse models of both early-stage and CNS African trypanosomiasis. Metabolism of DB844 in human liver microsomes (HLM) was investigated using liquid chromatography-mass spectrometry (LC-MS/MS). The metabolism of DB844 in HLM was NADPH-dependent and resulted in the production of eight metabolites over a 90?min incubation. O-Demethylation and N-dehydroxylation reactions resulted in the metabolic conversion of DB844 to its active DB820 metabolite. Chromatographic conditions used for LC-MS analysis allowed for the separation and identification of all metabolites including positional isomers. Demethylation of either the phenyl or pyridine side of DB844 (DB844 m/z 366.2) resulted in the production of two metabolites (M1A, M1B), each with a molecular ion of m/z of 352.3 and MS(2) fragments of 288.1, 305.2, 321.2 and 335.2. However, the intensities of the MS(2) fragments were different among the two isomeric metabolites, and comparison to an authentic standard allowed for the structural determination of each metabolite. The isomeric metabolites M2A and M2B, resulting from amidoxime reductions of M1A and M1B, were also chromatographically separated and had distinguishable MS(2) profiles that allowed for their structural assignments when compared to an authentic standard. The di-amidoxime product resulting from O-demethylation of either side of DB844 was also identified as an abundant metabolite during microsomal incubations. The active antitrypanosomal metabolite, DB820, was the last metabolite to be formed and thus provides evidence that DB844 may effectively be metabolized to its active metabolite in vivo.

Administration, Oral↗
PubMed2005

Controlled drug delivery systems based on thiolated chitosan microspheres.

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 microM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 microm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 microM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.

Chitin↗
PubMed1992

FTIR study of specific binding interactions between DNA minor groove binding ligands and polynucleotides.

The use of FTIR spectroscopy is made to study the interactions between polynucleotides and two series of minor groove binding compounds. The latter were developed and described previously as part of an ongoing program of rational design of modified ligands based on naturally occurring pyrrole amidine antibiotic netropsin, and varying the structure of bisbenzimidazole chromosomal stain Hoechst 33258. Characteristic IR absorptions due to the vibrations of thymidine and cytosine keto groups in polynucleotides containing AT and GC base pairs respectively are used to monitor their interaction with the added ligands. Although the two thiazole based lexitropsins based on netropsin structure differ in the relative orientation of nitrogen and sulfur atoms with respect to the concave edge of the molecules, they interact exclusively with the thymidine C2 = O carbonyl groups in the minor groove of the alternating AT polymer as evidenced by specific changes in the IR spectra. In the second series of compounds based on Hoechst 33258, the structure obtained by replacing the two benzimidazoles in the parent compound by a combination of pyridoimidazole and benzoxazole, exhibits changes in the carbonyl frequency region of poly dG.poly dC which is attributed to the ligand interaction at the minor groove of GC base pairs. In contrast, Hoechst 33258 itself interacts only with poly dA.poly dT. Weak or no interaction exists between the ligands and any of the polynucleotides at the levels of the phosphate groups or the deoxyribose units.

Bisbenzimidazole↗
PubMed2004

Pharmacomodulation of a sulfamide 5-HT6 receptor ligand.

A series of N-omega-aminoalkyl- or N-omega-amidinoalkyl-2,4,6-triisopropyl benzenesulfonamides has been synthesized and their respective affinity indices on 5-HT6 receptor determined. This evaluation clearly showed that the compounds possessing an arylpiperazine moiety or an amidine function exhibited good affinity for the model.

Drug Design↗