Plant experiments on the bioavailability of unextracted [carbonyl-14C]methabenzthiazuron residues from soil.
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Benzothiazoles↗
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Results for “Methylurea Compounds”
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A deuterium isotope effect on the inhibition of gastric secretion by N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea. Synthesis of metabolites.
The use of isotopic substitution to retard the oxidative metabolism of the gastric antisecretory agent N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (1) and improve its antisecretory potency was examined. The pyridine ring methyl hydrogens of 1 were replaced with either deuterium or fluorine. The hexadeuterated analogue (12) was found to be approximately 2.1 times more potent than the protio form (1) as an inhibitor of gastric acid secretion stimulated by gastrin tetrapeptide. The hexafluoro analogue (11) was 0.4 times as potent as 1. A useful pyridine ring synthesis was developed to prepare the metabolites of 1, 10a (4-hydroxymethyl) and 10b (6-hydroxymethyl), and the hexafluoro analogue 11. These syntheses involved the condensation of 1,3-diketones with an appropriately N-substituted amidinoacetate.
Animals↗
2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis.
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.
Antiviral Agents↗
A potent, orally bioavailable benzazepinone growth hormone secretagogue.
The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 +/- 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.
Administration, Oral↗
QXP: powerful, rapid computer algorithms for structure-based drug design.
New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An additional fast search step is introduced between the initial perturbation and energy minimization. The fast search produces approximate low-energy structures, which are likely to minimize to a low energy. For template fitting, QXP uses a superposition force field which automatically assigns short-range attractive forces to similar atoms in different molecules. The docking algorithms were evaluated using X-ray data for 12 protein-ligand complexes. The ligands had up to 24 rotatable bonds and ranged from highly polar to mostly nonpolar. Docking searches of the randomly disordered ligands gave rms differences between the lowest energy docked structure and the energy-minimized X-ray structure, of less than 0.76 A for 10 of the ligands. For all the ligands, the rms difference between the energy-minimized X-ray structure and the closest docked structure was less than 0.4 A, when parts of one of the molecules which are in the solvent were excluded from the rms calculation. Template fitting was tested using four ACE inhibitors. Three ACE templates have been previously published. A single run using QXP generated a series of templates which contained examples of each of the three. A pseudo-receptor, complementary to an ACE template, was built out of small molecules, such as pyrrole, cyclopentanone and propane. When individually energy minimized in the pseudo-receptor, each of the four ACE inhibitors moved with an rms of less than 0.25 A. After random perturbation, the inhibitors were docked into the pseudo-receptor. Each lowest energy docked structure matched the energy-minimized geometry with an rms of less than 0.08 A. Thus, the pseudo-receptor shows steric and chemical complementarity to all four molecules. The QXP program is reliable, easy to use and sufficiently rapid for routine application in structure-based drug design.
Algorithms↗
Biodegradation of the phenylurea herbicide isoproturon and its metabolites in agricultural soils.
Degradation of the phenylurea herbicide isoproturon (3-(4-isopropylphenyl)-1,1-dimethylurea) and several phenylurea and aniline metabolites was studied in agricultural soils previously exposed to isoproturon. The potential for degradation of the demethylated metabolite 3-(4-isopropylphenyl)-1-methylurea in the soils was much higher compared to isoproturon. In the most active soil only 6% of added 14C-labelled isoproturon was mineralised to 14CO2 within 20 days while in the same period 45% of added 14C-labelled 3-(4-isopropylphenyl)-1-methylurea was mineralized. This indicates that the initial N-demethylation may be a limiting step in the complete mineralization of isoproturon. Repeated addition of 3-(4-isopropylphenyl)-1-methylurea to the soil and further subculturing in mineral medium led to a highly enriched mixed bacterial culture with the ability to mineralize 3-(4-isopropylphenyl)-1-methylurea. The culture did not degrade either isoproturon or the didemethylated metabolite 3-(4-isopropylphenyl)-urea when provided as sole source of carbon and energy. The metabolite 4-isopropyl-aniline was also degraded and utilised for growth, thus indicating that 3-(4-isopropylphenyl)-1-methylurea is degraded by an initial cleavage of the methylurea-group followed by mineralization of the phenyl-moiety. Several attempts were made to isolate pure bacterial cultures degrading 3-(4-isopropylphenyl)-1-methylurea or 4-isopropyl-aniline, but they were not successful.
Biodegradation, Environmental↗
Effect of cholesterol on the non-electrolyte permeability of planar lecithin membranes.
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Acetamides↗
Membrane action of DMSO and other chemical inducers of Friend leukaemic cell differentiation.
DMSO and other cryoprotective agents produce a pronounced increase on the phase transition temperature of phospholipid membranes, indicating an increased stability. The effects of DMSO and other cryoprotective agents, divalent cations, and local anaesthetics on the transition temperature of phospholipid membranes seem to correlate with their effects on the differentiation of Friend leukaemic cells in vitro. These studies suggest that the induction of differentiation by cryoprotective agents may be the result of the interaction of these agents with cell membranes.
Anesthetics, Local↗
Dimethylthiourea inhibition of B16 melanoma growth and induction of phenotypic alterations; relationship to ATP levels.
1,3 Dimethylthiourea (DMTU) has previously been shown by us to inhibit the growth of melanoma cells and to induce phenotypic alterations in these cells, including ultrastructural alterations of mitochondria. These findings raised the possibility that impaired mitochondrial function might be involved in mediating the effect of DMTU on cell growth and phenotypic expression. The present study indicates that DMTU as well as another growth inhibitory methylurea derivative, tetramethylurea (TMU) significantly decrease ATP content in the B16 melanoma cell line. 1,3 Dimethylurea (1,3DMU) and 1,1 dimethylurea (1,1DMU) which are poor growth inhibitors, do not reduce ATP content significantly. Altered energy metabolism in the DMTU-treated cells is reflected by inhibition of the activity of cytochrome c oxidase and by increased lactate levels. A cell line selected for resistance to growth inhibition by DMTU was shown to be completely resistant to induction of phenotypic alterations by DMTU. These cells possess high lactate levels, high ATP content and a somewhat decreased Na/K ATPase activity as compared to wild type B16 F10 cells. 1,3 DMTU treatment of the resistant cells leads to a decrease in the activity of the mitochondrial enzyme cytochrome c oxidase, similar to its effect on the wild type B16 F10 cells. DMTU also reduces ATP content moderately in the resistant cells. However, the levels of ATP do not decrease beyond those found in untreated B16 F10 wild type cells. Taken together the results suggest that decreased ATP content might be involved, at least partially, in mediating the effects of DMTU on B16 melanoma cell growth and phenotypic expression.
Adenosine Triphosphate↗
Enrichment and analysis of peptide subsets using fluorous affinity tags and mass spectrometry.
Although mass spectrometry has become a powerful tool for the functional analysis of biological systems, complete proteome characterization cannot yet be achieved. Instead, the sheer complexity of living organisms demands fractionation of cellular extracts to enable more targeted analyses. Here, we introduce the concept of "fluorous proteomics," whereby specific peptide subsets from samples of biological origin are tagged with perfluorinated moieties and subsequently enriched by solid-phase extraction over a fluorous-functionalized stationary phase. This approach is extremely selective, yet can readily be tailored to enrich different subsets of peptides. Additionally, this methodology overcomes many of the limitations of traditional bioaffinity-based enrichment strategies, while enabling new affinity enrichment schemes impossible to implement with bioaffinity reagents. The potential of this methodology is demonstrated by the facile enrichment of peptides bearing particular side-chain functionalities or post-translational modifications from tryptic digests of individual proteins as well as whole cell lysates.
Affinity Labels↗
Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy.
Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment.
Animals↗
Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase.
A major problem in the development of antiviral therapies for AIDS has been the emergence of drug resistance. We report an analysis of the structure of a Val 82 to Ala mutant of HIV-1 proteinase complexed to A-77003, a C2 symmetry-based inhibitor. Modelling studies predicted that the V82A mutation would result in decreased van der Waals' interactions with the phenyl rings of A-77003 in both S1 and S1' subsites. Unexpected rearrangements of the protein backbone, however, resulted in favourable re-packing of inhibitor and enzyme atoms in the S1 but not the S1' subsite. This analysis reveals the importance of enzyme flexibility in accommodating alternate packing arrangements, and can be applied to the re-design of inhibitors targeted to drug resistant variants which emerge in the clinic.
Antiviral Agents↗
Enzyme immunoaffinity chromatography--a rapid semi-quantitative immunoassay technique for screening the presence of isoproturon in water samples.
Immunochromatography devices based on the principles of affinity chromatography and enzyme immunoassay have been developed to illustrate the possibility of providing extra-laboratory 'in the field' tests for pesticide monitoring. Isoproturon was chosen in this study as an example though other pesticides could have been used provided a suitable antiserum existed. The test system was prepared by immobilising isoproturon antibodies to porous silica which were then packed into disposable columns (immunoaffinity columns). The addition of chromagen-substrate 3,3',5,5'-tetramethylbenzidine into the immunoaffinity columns, after the application of a mixture containing an equal volume of isoproturon samples or isoproturon standard solutions with a fixed concentration of isoproturon labelled with horseradish peroxidase, allowed the development of a colorimetric portable assay capable of screening samples qualitatively for the presence of isoproturon in water. Samples with contamination levels of 0.12 microgram l-1 isoproturon and above were visually identified as positive samples in comparison to the zero standard sample. However, samples with concentrations below this level would be considered as negative (no isoproturon present at this limit of detection). The duration of the sample screening procedure on the column was less than 25 min making the technique highly suitable for a rapid estimate of isoproturon concentrations. Furthermore, the system could estimate isoproturon concentrations in water from various sources with no requirement for sample preparation. Therefore, the technique is ideally suited for monitoring the presence of pesticides in water. Further refinement of the assay could result in a test suitable for use by non-skilled personnel in extra-laboratory locations (e.g., a mobile or field laboratory).
Chromatography, Affinity↗
Development of an enzyme-linked immunosorbent assay for isoproturon in water.
A competitive enzyme-linked immunosorbent assay (ELISA) suitable for the determination of the urea herbicide isoproturon [3-(4-isopropylphenyl)-1,1-dimethyl urea] in water has been developed. A derivative of isoproturon [3-(4-isopropylphenyl)-1-carboxypropyl-1-methyl urea] has been synthesized and linked to thyroglobulin using the N-hydrosuccinimide reaction. The immunogen was used to immunize two sheep, which both responded by producing specific antibodies to isoproturon with little cross-reactivity to various structurally related and unrelated pesticides. The enzyme label was prepared by coupling the hapten to horseradish peroxidase using the above reaction. The coated-antibody competitive ELISA, which has a sensitivity of 0.03 microgram l-1, permits the direct determination of isoproturon in various water matrices and can facilitate the monitoring of water quality in drinking-water supplies.
Animals↗
Preparation and activity of guanidinated or acetylated erabutoxins.
1. Erabutoxins, a, b and c, neurotoxic proteins of a sea snake Lacticauda semifasciata, were guanidinated with O-methylisourea. The amino groups of all the lysine residues and those at the N-termini of the toxins were modified. The lethal activity of the toxins decreased to 50% (erabutoxins a and b) or 17% (erabutoxin c) of the original value on the modification. The c.d. (circular dichroism) maximum at 227 nm of the modified toxins became lower, whereas the whole profile of the c.d. curve remained unchanged. 2. The amino groups of erabutoxin b were acetylated with acetic anhydride. All the five monoacetyl derivatives were isolated from the reaction products by CM-cellulose and Bio-Rex 70 column chromatography. [1-Nalpha-acetylarginine]-, [15-N6-acetyl-lysine]- and [51-N6-acetyl-lysine]-erabutoxin b retained the toxicity of the native toxin, whereas [27-N6-acetyl-lysine] and [47-N6-acetyl-lysine]-erabutoxin b were 17 and 8% active respectively. The overall profile of c.d. spectrum of erabutoxin b remained unchanged on the monoacetylation.
Acetylation↗
Very low density lipoprotein apo beta 100--comparison of several methods for protein assay.
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Apolipoprotein B-100↗
Isolation of isoproturon-degrading bacteria from treated soil via three different routes.
Three different isolation routes (flask enrichment/flask degradation assay, flask enrichment/microplate degradation assay, MPN assay/microplate degradation assay) were used to obtain pure cultures of bacteria which degraded isoproturon (3-(4-isopropylphenyl)-1,1-dimethylurea) as sole carbon and nitrogen source in a mineral salts medium from a field soil treated with isoproturon in the laboratory. All three isolation routes were successful, but the microplate assay of degradation was more successful than the flask assay. Characterization of 36 isolates indicated that they formed 16 distinct phenotypes (10 Gram-positive phenotypes, six Gram-negative phenotypes) which are likely to represent distinct species. Low concentrations of the degradation product 3-(4- isopropylphenyl)-1-methylurea (IPPMU) were occasionally found in the culture solutions. When provided as the sole source of carbon and nitrogen, the monomethyl degradation product was itself rapidly degraded by several of the isolates. Some isolates were also able to use the demethylated degradation product 3-(4-isopropylphenyl)-urea (IPPU) as sole source of carbon and nitrogen, although there was occasionally an extended lag-phase before rapid degradation commenced. One isolate was particularly active and degraded isoproturon, the monomethyl and demethylated degradation products of isoproturon, and demethylated the related phenylureas diuron and linuron.
Bacteria↗
Expression and presence of septal neurokinin-2 receptors controlling hippocampal acetylcholine release during sensory stimulation in rat.
We examined the expression and presence of NK2 receptors in the septal area of rat brain, and investigated their functional role in the regulation of the septohippocampal cholinergic system. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we showed the presence of NK2 receptor mRNA expression in the septal area, and detected septal NK2 binding sites by using a fluorescent-tagged neurokinin A (NKA) derivative. In vivo microdialysis was employed to explore the functional role of NK2 receptors in the release of hippocampal acetylcholine evoked by tactile stimulation in freely moving rats. Two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, produced a marked and reproducible increase in hippocampal acetylcholine release. This effect was dose-dependently prevented by intraperitoneal administration of the two selective non-peptide tachykinin NK2 receptor antagonists SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3 and 1 mg/kg, i.p.), but not by the inactive enantiomer of SR48968 (SR48965, 1 mg/kg) nor by the two non-peptide NK1 receptor antagonists SR140333 (3 mg/kg, i.p.) and GR205171 (1 mg/kg, i.p.). Furthermore, the intraseptal application of SR144190 (10(-8) M) reduced the sensory response. Finally, intraseptal perfusion of neurokinin A (0.01-10 microM) in anaesthetized rats produced a concentration-dependent increase in hippocampal acetylcholine release. The response to neurokinin A (0.1 microM) was prevented by SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3-1 mg/kg, i.p.). In conclusion, this study provides direct evidence for the role of endogenous NKA/substance P, through the activation of NK2 receptors, in regulating the septohippocampal cholinergic function.
Acetylcholine↗