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PubMed2006

Theoretical studies of the transition-state structures and free energy barriers for base-catalyzed hydrolysis of amides.

The transition-state structures and free energy barriers for the rate-determining step (i.e. the formation of a tetrahedral intermediate) of base-catalyzed hydrolysis of a series of amides in aqueous solution have been studied by performing first-principle electronic structure calculations using a hybrid supermolecule-polarizable continuum approach. The calculated results and a revisit of recently reported experimental proton inventory data reveal that the favorable transition-state structure optimized for the tetrahedral intermediate formation of hydroxide ion-catalyzed hydrolysis of formamide may have three solvating water molecules remaining on the attacking hydroxide oxygen and two additional water molecules attached to the carbonyl oxygen of formamide. The calculated results have also demonstrated interesting substituent effects on the optimized transition-state geometries, on the transition-state stabilization, and on the calculated free energy barriers for the base-catalyzed hydrolysis of amides. When some or all of the hydrogen atoms of formamide are replaced by methyl groups, the total number of water molecules hydrogen-bonding with the attacking hydroxide in the transition state decreases from three for formamide to two for N-methylacetamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMA). The larger substituents of the amide hinder the solvent water molecules approaching the attacking hydroxide oxygen in the transition state and, therefore, destabilize the transition-state structure and increase the free energy barrier. By using the optimized most favorable transition-state structures, the calculated free energy barriers, i.e., 21.6 (or 21.7), 22.7, 23.1, and 26.0 kcal/mol for formamide, N-methylacetamide, DMF, and DMA, respectively, are in good agreement with the available experimental free energy barriers, i.e., 21.2, 21.5, 22.6, and 24.1 kcal/mol for formamide, N-methylacetamide, DMF, and DMA, respectively.

Acetamides↗
PubMed2005

Fractal behavior of functionalized fullerene aggregates. I. Aggregation of two-handed tetraaminofullerene with DNA.

In tris-buffered saline (TBS) with a trace of dimethylformamide (DMF), the homoaggregation process of a functionalized fullerene, the two-handed tetraaminofullerene (TH), and the heteroaggregation process (complex formation) of TH with DNA (pGL3-control plasmid) were studied dynamically by using a combination of static and dynamic laser light scattering measurements. Fractal behavior was investigated in the aggregation process of both TH homoaggregates and TH-DNA heteroaggregates. The stability of aggregates in solution depends on the molar concentration ratio R(M), defined as the molar ratio of moles of TH to moles of the DNA base pair. Higher R(M) values resulted in lower aggregate stability. The transition of the fractal dimension (Df) in TH homoaggregation by rapidly mixing 3.78 microM TH with an equal volume of the blank buffer was found to vary from a value of 1.46 to 2.02. Dynamic light scattering results revealed that, in the aggregation process, the change in the size distribution of aggregates with time could be related to a Df transition. In the Df transition region, the size distribution of homoaggregates displayed a drastic change from a single-mode distribution to a bimodal distribution, which clearly suggested a restructuring process with the formation of large aggregates. When the aggregation process finally reached equilibrium, Df = 2.02, the size of the homoaggregates had a single mode but a broad distribution. However, TH-DNA heteroaggregation showed a Df transition from 1.58 to 1.7, but over a shorter time range of less than 5 min. Then, the Df value fluctuated in the range of 1.7 and finally reached an equilibrium value of Df approximately 1.78, which was independent of molar concentration. There are two main action forces involved in the heteroaggregation process: van der Waals forces and attractive electrostatic forces, with the latter one being stronger and faster than that of the former. Therefore, a two-step action could occur in the heteroaggregation process. In the beginning of mixing, the attractive electrostatic forces dictated the aggregation process, and then van der Waals forces also got involved in the entire aggregation process. By using an initial concentration of 3.78 microM each and R(M) = 1, TH-DNA heteroaggregates showed more stable solution behavior than the homoaggregates. The lower Df value of the heteroaggregates could be related to a looser compact structure. Results from scanning electron microscopy (SEM) also disclosed the different textures between TH homoaggregates and TH-DNA heteroaggregates; the former had a more dense packing than the latter one.

DNA↗
PubMedDate not supplied

N-alkylformamides are metabolized to N-alkylcarbamoylating species by hepatic microsomes from rodents and humans.

Hepatotoxic formamides such as N-methylformamide (NMF) and N,N-dimethylformamide (DMF) are metabolized in vivo to N-acetyl-S-(N-methylcarbamoyl)cysteine via oxidation at the formyl carbon, which yields a reactive intermediate. The hypothesis was tested that this biotransformation route can be studied in vitro with hepatic fractions. NMF was incubated with microsomes or cytosol obtained from BALB/c mice, and metabolically generated N-methyl-carbamoylating species were analyzed after derivatization with ethanol in base to furnish ethyl N-methylcarbamate. Generation of metabolite was catalyzed by microsomes, but not by cytosol. Detection of the N-methylcarbamoylating species was dependent on the presence in the incubation mixture of NMF, viable microsomes, NADPH, and a thiol-containing agent such as glutathione. Metabolite formation was inhibited by SKF 525-A (3 mM) and abolished when the incubation atmosphere consisted of an air/carbon monoxide mixture (1:1) instead of air. Metabolism was not induced by pretreatment of mice with phenobarbital or beta-naphthoflavone. N-Ethylformamide and the DMF metabolite N-(hydroxymethyl)-N-methylformamide, but not DMF, were metabolized by microsomes to the N-alkylcarbamoylating metabolite at a measurable rate. NMF metabolism was also observed with liver microsomes from Sprague-Dawley rats or from humans. In the case of rat microsomes the rate of metabolism was half of that measured with murine microsomes. The results suggest that (i) the metabolic toxification of NMF can be studied in hepatic microsomes and (ii) the oxidation of the formyl moiety in N-alkylformamides is catalyzed by cytochrome P-450.

Animals↗
PubMedDate not supplied

Deuterium isotope effect in the interaction of N-nitrosodimethylamine, ethanol, and related compounds with cytochrome P-450IIE1.

Deuteration of N-nitrosodimethylamine (NDMA) decreases its carcinogenicity and produces an isotope effect on its metabolism. Our previous results showed that deuteration causes a 5-fold increase in the apparent Km, but not the Vmax, for the demethylation and denitrosation of NDMA in microsomes. In the present work, we studied the nature of this deuterium isotope effect with several compounds using acetone-induced microsomes as a source of cytochrome P-450IIE1. In the microsomal N-nitrosodiethylamine deethylase reaction, NDMA and [2H6]NDMA were competitive inhibitors and displayed apparent Ki values of 59 and 441 mM, respectively, showing an isotope effect of 0.13. Similarly, in the p-nitrophenol hydroxylase reaction, a deuterium isotope effect of 0.21 on the Ki was observed. With acetone as an inhibitor for p-nitrophenol hydroxylase, the isotope effect on the Ki was 0.11. Similar deuterium isotope effects were also observed with acetone and dimethylformamide as competitive inhibitors for NDMA demethylase. When the oxidation of ethanol, [1,1-2H2]ethanol, [2,2,2-2H3]ethanol, and [2H6]ethanol was compared, an isotope effect of about 5 was found in the Vmax/Km due to the deuteration of the methylene group (carbon 1) but not due to the methyl group. However, the Vmax was not affected. A corresponding deuterium isotope effect was observed in the Ki when these compounds were used as competitive inhibitors for the NDMA demethylase reaction. The results demonstrate that deuteration of NDMA, ethanol, and related compounds results in an increase in the Km or Ki with little change in the Vmax of P-450IIE1-catalyzed reactions. The molecular basis of this isotope effect is discussed.

Acetone↗
PubMedDate not supplied

1,N2-ethenodeoxyguanosine: properties and formation in chloroacetaldehyde-treated polynucleotides and DNA.

1,N2-Etheno-2'-deoxyguanosine (1,N2-epsilon dGuo), not previously reported as a product of chloroacetaldehyde (CAA) reaction, has been synthesized and characterized. Reaction of deoxyguanosine with CAA in dimethylformamide in the presence of K2CO3 led to preparation of pure 1,N2-epsilon dGuo with 55% yield. pKa values are 2.2 and 9.2. The anionic form of the compound exhibits weak but defined fluorescence; the intensity is similar to that of N2,3-etheno-2'-deoxyguanosine (N2,3-epsilon dGuo) at neutrality. The stability of the glycosyl bond of 1,N2-epsilon dGuo (t1/2 = 2.3 h at 37 degrees C, pH 1) is 10-fold greater than of unmodified deoxyguanosine and at least one thousand-fold greater than of isomeric N2,3-epsilon dGuo. Reaction of CAA with model polynucleotides indicates that hydrogen bonding of guanine residues in the double-stranded structures is, as expected, an important factor in the formation of 1,N2-ethenoguanine. In contrast, the formation of isomeric N2,3-ethenoguanine is relatively independent of whether the DNA is single- or double-stranded. In salmon sperm DNA, reacted with CAA at neutrality, the formation of 1,N2-ethenoguanine could be demonstrated. However, we find the efficiency of formation of this adduct in double-stranded DNA to be lower than that of all other etheno derivatives.

Acetaldehyde↗
PubMed2004

Identification and characterization of novel stable deoxyguanosine and deoxyadenosine adducts of benzo[a]pyrene-7,8-quinone from reactions at physiological pH.

Benzo[a]pyrene (B[a]P) is an archetypal member of the family of polycyclic aromatic hydrocarbons (PAHs) and is a widely distributed environmental pollutant. B[a]P is known to induce cancer in animals, and B[a]P-containing complex mixtures are human carcinogens. B[a]P exerts its genotoxic and carcinogenic effects through metabolic activation forming reactive intermediates that damage DNA. DNA adduction by B[a]P is a complex phenomenon that involves the formation of both stable and unstable (depurinating) adducts. One pathway by which B[a]P can mediate genotoxicity is through the enzymatic formation of B[a]P-7,8-quinone (BPQ) from B[a]P-7,8-diol by members of the aldo-keto-reductase (AKR) family. Once formed, BPQ can act as a reactive Michael acceptor that can alkylate cellular nucleophiles including DNA and peptides. Earlier studies have reported on the formation of stable and depurinating adducts from the reaction of BPQ with DNA and nucleosides, respectively. However, the syntheses and characterization of the stable adducts from these interactions have not been addressed. In this study, the reactivity of BPQ toward 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) nucleosides under physiological pH conditions is examined. The identification and characterization of six novel BPQ-nucleoside adducts obtained from the reaction of BPQ and dG or dA in a mixture of phosphate buffer and dimethylformamide are reported. The structures of these adducts were determined by ultraviolet spectroscopy, electrospray mass spectrometry, and NMR experiments including (1)H, (13)C, two-dimensional COSY, one-dimensional NOE, ROESY, HMQC, HSQC, and HMBC. The reaction of BPQ with dG afforded four unique Michael addition products: two diastereomers of 8-N(1),9-N(2)-deoxyguanosyl-8,10-dihydroxy-9,10-dihydrobenzo[a]pyren-7(8H)-one (BPQ-dG(1,2)) and two diastereomers of 10-(N(2)-deoxyguanosyl)-9,10-dihydro-9-hydroxybenzo[a]pyrene-7,8-dione (BPQ-dG(3,4)). The BPQ-dG(1,2)( )()adducts suggest a 1,6-Michael addition reaction of dG, an oxidation of the hydroquinone to the quinone, a 1,4-Michael addition of water, and an internal cyclization. The BPQ-dG(3,4)( )()adducts suggest a 1,4-Michael addition reaction of dG, an oxidation of the hydroquinone to the quinone, and a 1,6-Michael addition of water. Under similar but extended reaction conditions, the reaction of BPQ with dA produced only one diastereomeric pair of adducts identified as 8-N(6),10-N(1)-deoxyadenosyl-8,9-dihydroxy-9,10-dihydrobenzo[a]pyren-7(8H)-one (BPQ-dA(1,2)). The BPQ-dA(1,2)( )()adducts suggest a 1,4-Michael addition reaction of dA, an oxidation of the hydroquinone to the quinone, a 1,6-Michael addition of water, and an internal cyclization. As considerable efforts have been placed in documenting the genotoxic effects of BPQ, this first report of the identification and characterization of these stable adducts of BPQ formed under physiological pH conditions is expected to contribute significantly to the area of BPQ-mediated genotoxicity and carcinogenesis.

Benzo(a)pyrene↗
PubMed1996

Reaction of mucochloric and mucobromic acids with adenosine and cytidine: formation of chloro- and bromopropenal derivatives.

Mucochloric (MCA) and mucobromic acid (MBA)--bacterial mutagens and water disinfection byproducts--were reacted with adenosine, cytidine, and guanosine in N,N-dimethylformamide (DMF). In the MCA reaction with adenosine and cytidine and in the MBA reaction with adenosine one major product was formed. In the reactions of MBA with cytidine and in the reactions of MCA and MBA with guanosine only trace levels of products could be detected, and these were not further characterized. The products from the adenosine and cytidine reactions were isolated by preparative chromatography on octadecylsilane columns and structurally characterized by UV absorbance, 1H and 13C NMR spectroscopy, and mass spectrometry. The products were identified as 3-(N6-adenosinyl)-2-chloro-2-propenal (MClA), 3-(N6-adenosinyl)-2-bromo-2-propenal (MBrA), and 3-(N4-cytidinyl)-2-chloro-2-propenal (MClC). The yields of MClA, MBrA, and MClC were 19, 4 and 7 mol %, respectively. These halopropenal derivatives were formed also in reactions carried out in aqueous solutions at pH 7.4 and 37 degrees C at low yields, about 5 x 10(-3)%. The mechanism of formation of the halopropenal derivatives and of the previously identified etheno and ethenocarbaldehyde derivatives was elucidated by reacting 13C-3 labeled MCA with adenosine in DMF and in water. The location of the labeled carbon in the products was determined from the 13 C NMR spectra. It was concluded that the halopropenal derivatives were formed by mechanisms that differ completely from the one responsible for the formation of the propenal adducts (M1A and M1C) previously reported to be formed in reactions of malonaldehyde with adenosine and cytidine.

Adenosine↗
PubMed1999

Synthesis and structure determination of the adducts formed by electrochemical oxidation of Dibenzo[a,l]pyrene in the presence of adenine.

Because the radical cations of polycyclic aromatic hydrocarbons (PAH) are involved in tumor initiation, determination of the structures of biologically formed PAH-DNA adducts is important and relies on comparison of their properties with those of synthesized adducts. One of the possible sites of adduct formation is the N-3 position of Ade, but this depurinating adduct is not obtained by one-electron oxidation of dibenzo[a,l]pyrene (DB[a,l]P) in the presence of deoxyadenosine. Therefore, we turned to electrochemical oxidation of DB[a,l]P in the presence of Ade in dimethylformamide and produced the following adducts: DB[a,l]P-10-N1Ade (47%), DB[a, l]P-10-N3Ade (5%), DB[a,l]P-10-N7Ade (2%), and DB[a,l]P-10-N(6)Ade (6%). In Me(2)SO, this reaction afforded the same four adducts, but in slightly different yields: DB[a,l]P-10-N1Ade (44%), DB[a, l]P-10-N3Ade (9%), DB[a,l]P-10-N7Ade (1%), and DB[a,l]P-10-N(6)Ade (3%). These adducts were purified by reverse-phase HPLC, and the subtle differences between the isomers were revealed by NMR, tandem mass spectrometry, and fluorescence line-narrowing spectroscopy. The relative yields of the N1Ade, N3Ade, and N7Ade adducts reflect the nucleophilicity and steric accessibility of these three nitrogen atoms in Ade.

Adenine↗
PubMed1997

Inulin hydrogels as carriers for colonic drug targeting: I. Synthesis and characterization of methacrylated inulin and hydrogel formation.

PURPOSE: Vinyl groups were introduced in inulin chains in order to form hydrogels of this sugar polymer by free radical polymerization. METHODS: Inulin was reacted with glycidyl methacrylate in N,N-dimethylformamide in the presence of 4-dimethylaminopyridine as catalyst. 1H and 13C NMR spectroscopy were used for the characterization of the obtained reaction product. Solid state 13C NMR spectroscopy revealed the conversion of the incorporated vinyl groups into covalent cross-links upon free radical polymerization of aqueous solutions of the derivatized inulin. RESULTS: During reaction of inulin with glycidyl methacrylate, transesterification occurred, leading to the direct attachment of the methacryloyl group to inulin. Consequently, the obtained reaction product is methacrylated inulin. The extent of chemical modification of inulin could be tuned by varying the molar ratio of glycidyl methacrylate to inulin in the reaction mixture. Aqueous solutions of methacrylated inulin were converted into cross-linked hydrogels by free radical polymerization using ammonium persulphate and N,N,N',N'-tetramethylethylenediamine as initiating system. CONCLUSIONS: Inulin hydrogels can be formed by free radical polymerization of aqueous solutions of methacrylated inulin.

4-Aminopyridine↗
PubMed1992

Relationship of myc protein expression to the phenotype and to the growth potential of HOC-7 ovarian cancer cells.

In this investigation we demonstrate expression of myc oncoproteins in HOC-7 ovarian adenocarcinoma cells. The cells were exposed to differentiation inducing agents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), retinoic acid (RA) and transforming growth factor-beta 1 (TGF-beta 1). Myc protein expression in treated cells was then compared with that in control cultures and in monoclonal HOC-7 sublines, which are characterised by distinct phenotypes. Cells exposed to DMSO and DMF became markedly enlarged and flattened and developed cytoplasmic extensions. They looked similar to a subline, which revealed a less malignant and more differentiated cell phenotype. All four inducers prolonged the cell doubling time and reduced the saturation density to levels, normally found in the more differentiated subline. Furthermore, all inducers except RA elevated extracellular fibronectin, which is characteristic for less malignant epithelial cell phenotypes. All four agents inhibited myc oncoprotein expression reversibly (1% DMSO greater than 0.5% DMF greater than 10 microM RA greater than 10 ng ml-1 TGF-beta 1) and in time-dependent manner. Down-regulation of myc protein expression is, therefore, closely related to inducer-dependent growth reduction of HOC-7 cells and to the development of a less malignant cell phenotype.

Actins↗
PubMed1991

Enzyme engineering for nonaqueous solvents: random mutagenesis to enhance activity of subtilisin E in polar organic media.

Enzyme activity is often dramatically reduced in polar organic solvents, even under conditions where the folded structures are stable. We have utilized random mutagenesis by polymerase chain reaction (PCR) techniques combined with screening for enhanced activity in the presence of dimethylformamide (DMF) to probe mechanisms by which improved enzymes for chemical synthesis in polar organic media might be obtained. Two amino acid substitutions which enhance subtilisin E activity in the presence of DMF, Q103R and D60N, were identified by screening on agar plates containing DMF and casein. The two substitutions are located near the substrate binding pocket or in the active site, and their effects on the catalytic efficiency kcat/KM for the hydrolysis of a peptide substrate are additive. The effects of D60N are apparent only in the presence of DMF, highlighting the importance of screening in the organic solvent. Protein engineering is an effective approach to enhancing enzyme activity in organic media: the triple mutant D60N + Q103R + N218S is 38 times more active than wild-type subtilisin E in 85% DMF. An evolutionary approach consisting of multiple steps of random mutagenesis and screening in continually higher concentrations of organic solvent should result in enzymes that are substantially more active in organic media.

Amidohydrolases↗
PubMed2004

Synthesis of protoheme IX derivatives with a covalently linked proximal base and their human serum albumin hybrids as artificial hemoprotein.

The simple one-pot reaction of protoporphyrin IX and omega-(N-imidazolyl)alkylamine or O-methyl-L-histidyl-glycine with benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate at room temperature produced a series of protoporphyrin IX species with a covalently linked proximal base at the propionate side-chain. The central iron was inserted by the general FeCl2 method, converting the free-base porphyrins to the corresponding protoheme IX derivatives. Mesoporphyrin IX and diacetyldeuteroporphyrin IX analogues were also prepared by the same procedure. The Fe(II) complexes formed dioxygen (O2) adducts in dimethylformamide at 25 degrees C. Some of them were incorporated into the hydrophobic domain of recombinant human serum albumin (rHSA), providing albumin-heme hybrids (rHSA-heme), which can bind and release O2 in aqueous media (pH 7.3, 25 degrees C). The oxidation process of converting the dioxygenated heme in rHSA to the inactive Fe(III) state obeyed first-order kinetics, indicating that the mu-oxo dimer formation was prevented by the immobilization of heme in the albumin scaffold. The rHSA-heme, in which the histidylglycil tail coordinates to the Fe(II) center, showed the most stable O2 adduct complexes.

Dimethylformamide↗
PubMed2003

Removal of gutta-percha from root canals using an Nd:YAG laser.

AIM: To examine the use of an Nd:YAG laser in removing gutta-percha fillings from root canals when used in conjunction with eucalyptol, dimethylformamide (DMF) or no solvent. METHODOLOGY: Root-canal fillings (sealer and gutta-percha) were removed with laser irradiation of 20 Hz/1.5 W from 30 roots randomly divided in three groups. In group 1, the solvent was eucalyptol; in group 2, the solvent was DMF; and in group 3, no solvent was used. Laser irradiation was performed until the temperature measured on the root surface increased by 4 degrees C over room temperature. The treatment was deemed complete when the apical foramen was reached with the optical fibre and a reamer. The samples were split longitudinally, and the area of remaining gutta-percha on the root-canal walls was determined with the aid of a computer program. The total number of laser pulses to achieve length and the highest temperature recorded was determined for each tooth. The results were statistically analysed using Student's t-test (P < 0.05) for independent samples. RESULTS: The average temperature increase in group 1 was 9.17 +/- 0.56 degrees C; in group 2, 9.56 +/- 0.28 degrees C; and in group 3, 8.29 +/- 0.41 degrees C. The shortest time to achieve length was in group 3 (6.4 +/- 0.49 min), then in group 1 (6.7 +/- 0.85 min) and group 2 (7.05 +/- 0.79 min). The area of remaining gutta-percha was the largest in group 2 (6.13 +/- 5.76%), whilst the smallest was for group 3 (4.69 +/- 4.03%), but the difference was not statistically significant. The number of pulses was not statistically significant between the groups. CONCLUSIONS: Use of an Nd:YAG laser alone is capable of softening gutta-percha. The addition of solvents did not improve the retreatment, either in terms of the time required for the procedure or in terms of the area of remaining gutta-percha on root-canal walls.

Aluminum Silicates↗
PubMed1998

Characterization of the antinociceptive and sedative effect of amitraz in horses.

Amitraz, an acaricide used to control ectoparasites in animals has a complex pharmacological activity, including alpha2-adrenergic agonist action. The purpose of this research was to investigate the possible antinociceptive and/or sedative effect of amitraz in horses. The sedative effect of the intravenous (i.v.) injection of dimethylformamide (DMF, 5 mL, control) or amitraz (0.05, 0.10, 0.15 mg/kg), was investigated on the head ptosis test. The participation of alpha2-adrenergic receptors in the sedative effect provoked by amitraz was studied by dosing yohimbine (0.12 mg/kg, i.v.). To measure the antinociception, xylazine hydrochloride (1 mg/kg, i.v., positive control) and the same doses of amitraz and DMF were used. A focused radiant light/heat directed onto the fetlock and withers of a horse were used as a noxious stimulus to measure the hoof withdrawal reflex latency (HWRL) and the skin twitch reflex latency (STRL). The three doses of amitraz used (0.05, 0.10 and 0.15 mg/kg) provoked a dose-dependent relaxation of the cervical muscles. The experiments with amitraz and xylazine on the HWRL showed that after i.v. administration of all doses of amitraz there was a significant increase of HWRL up to 150 min after the injections. Additionally, there was a significant difference between control (DMF) and positive control (xylazine) values up to 30 min after drug injection. On the other hand, the experiments on the STRL show that after administration of amitraz at the dose of 0.15 mg/kg, a significant increase in STRL was observed when compared with the control group. This effect lasted up to 120 min after injection. However, no significant antinociceptive effect was observed with the 0.05 and 0.10 mg/kg doses of amitraz or at the 1.0 mg/kg dose of xylazine.

Adrenergic alpha-Agonists↗
PubMed2006

Molecular dynamics of polystyrene solutions in microwave fields.

Equilibrium and nonequilibrium molecular dynamics simulation techniques were used to assess the influence of an applied microwave field on the dynamics of methylamine-methanol and methylamine-dimethylformamide (DMF) solutions bound within atactic polystyrene over a range of polymer densities from 35 to 96 wt % polymer. Atomistically detailed systems were studied, ranging from 3000 to 10 644 particles, using previously established potential models. Structural and dynamical properties were determined in the canonical (NVT) ensemble at 298 K. The simulated DMF self-diffusion coefficients in polystyrene solutions were compared with the zero-field experimental results established with pulsed-gradient spin-echo NMR spectrometry. A simulated external microwave field, with a rms electric field intensity of 0.1 VA, was applied to these systems and the simulated dynamical results over field frequencies up to 10(4) GHz were compared with the zero-field values. Simulated evidence of athermal effects on the diffusive characteristics of these mixtures is reported.

Chemistry, Physical↗
PubMed1974

Noncovalent modification of deoxyhemoglobin S solubility and erythrocyte sickling.

Ammonium sulfate, as well as potassium phosphate, can be used to measure solubility differences between hemoglobin S and hemoglobin A. In addation, the solubility of deoxyhemoglobin C(Harlem) in 1.96 M phosphate has a markedly different temperature dependence from that of deoxyhemoglobin S. This observation indicates that the solubility measurement is quite sensitive to changes in protein structure. Because of the large degree of comparability between the solubility and the aggregation of deoxyhemoglobin S, solubility was used to measure the effectiveness of organic compounds as noncovalent modifiers of deoxyhemoglobin S aggregation. Organic solvents (ethanol, dimethylsulfoxide, 1,4-dioxane, dimethylformamide) alter the solubility characteristics of deoxyhemoglobin S in 1.96 M phosphate buffer, pH 7.0. The concentrations of solvent necessary to provide a half-maximal effect are remarkably similar (about 0.5 M), although the chemical nature of these compounds is quite different. The effect of these solvents must be to prevent the noncovalent bond formation necessary to produce the insoluble hemoglobin precipitate, perhaps by altering the water structure around the deoxyhemoglobin S molecules. In addition to these organic solvents, guanidine hydrochloride and urea, two well-known protein denaturants, were studied. Guanidine hydrochloride was as effective as the best organic solvent in increasing the solubility of deoxyhemoglobin S; urea was far less effective. Studies in vitro with intact erythrocytes from individuals homozygous for hemoglobin S showed that sickling is decreased up to 50% by treatment with ethanol. This offers further evidence that solubility is monitoring a phenomenon similar to the aggregation of deoxyhemoglobin S inside erythrocytes. While use of these particular compounds in vitro would seem to have no clinical implications, these studies do suggest that the use of chemicals that do not modify hemoglobin S covalently should be explored in efforts to prevent deoxyhemoglobin S aggregation.

Ammonium Sulfate↗
PubMed1979

Inducers of mammalian cell differentiation stimulate dome formation in a differentiated kidney epithelial cell line (MDCK).

Cell cultures of a differentiated kidney epithelial cell line, MDCK, spontaneously form fluid-filled domes or hemicysts composed of numbers of cells as a manifestation of specialized epithelial transport phenomena. Addition to MDCK cells of a broad spectrum of compounds that are known as potent inducers of mammalian cell differentiation in cell culture caused a striking increase in the frequency of dome formation. Polar compounds such as N,N-dimethylformamide, dimethyl sulfoxide, or hexamethylene bisacetamide stimulated increased dome formation 15--30 hr after addition. Induction of domes by these compounds was prevented either by inhibitors of protein synthesis or by ouabain, cytochalasin B, or vinblastine. Inhibition of DNA synthesis did not block chemical induction of domes. Other inducers were compounds of physiological occurrence such as n-butyrate or adenosine. Furthermore, a variety of conditions expected to elevate intracellular levels of cyclic AMP also stimulated dome formation. These findings suggest the hypothesis that domes are formed in cell culture by a form of cell differentiation that is under positive control by cyclic AMP.

Acetamides↗