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At least 739 records · Page 41Linked to original sources
PubMed2002

Solubility, ionization, and partitioning behavior of unsymmetrical disulfide compounds: alkyl 2-imidazolyl disulfides.

Alkyl 2-imidazolyl disulfide compounds are novel antitumor agents, one of which is currently being evaluated in Phase I clinical trials. These molecules contain an unsymmetrical disulfide fragment, the lipophilic and electronic contributions of which are still not defined in the literature. Lipophilicity, ionization, and solubility of a number of alkyl 2-imidazolyl disulfides were studied. Based on the additivity of lipophilicity and ionization properties, the contribution of the unsymmetrical disulfide fragment to lipophilicity and ionization was elucidated. The unsymmetrical disulfide fragment contributed a Rekker's hydrophobic constant of 0.761 to the lipophilicity of these compounds and an approximated Hammett constant (sigma) of 0.30 to their ionization. The applicability of the general solubility equation (GSE) proposed by Jain and Yalkowsky in predicting the aqueous solubility of these analogs was evaluated. The GSE correctly ranked the aqueous solubilities of these compounds and estimated their log molar solubilities with an average absolute error of 0.35.

Disulfides↗
PubMed2003

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant.

Recent studies in a conscious dog model demonstrated intestinal lymphatic transport to be a significant contributor to the bioavailability of the highly lipid-soluble free-base of halofantrine (Hf), and surprisingly, also the poorly lipid-soluble hydrochloride salt (Hf. HCl). Partial conversion of solubilized Hf. HCl to Hf base within the intestinal lumen prior to the lymphatic uptake seemed to be the most likely explanation for these results. This hypothesis was supported by studies exploring the partitioning behavior of Hf. HCl between soybean oil (SBO) and aqueous micellar solutions containing different ionic and nonionic surfactants. Mixed micelles prepared from sodium taurodeoxycholate (NaTC) and lecithin (PC) were chosen to represent fed-state intestinal fluids. The apparent ionization constants derived from the partitioning versus pH profiles showed marked shifts when compared with the likely aqueous pK(a) value. In the present paper, the apparent pK(a) values of Hf in aqueous micellar phases, without a coexisting oil phase, were investigated to further probe the mechanisms underlying the effect of micellar media on the apparent ionization equilibrium, and subsequently, on its partitioning behavior in the triphasic systems. Another aim of this study was to further evaluate the aqueous pK(a) value of Hf. The results indicate that the aqueous pK(a) of Hf is most probably in the range approximately 8-9, and that the ionization equilibrium is highly dependent on the solution environment. For example, marked pK(a) shifts of several units were observed for Hf in the presence of different micellar species and SBO. The apparent ionization equilibrium depends not only on interaction of Hf with the micelles, but also on its partitioning into the oil phase.

Antimalarials↗
PubMed1976

Phenylbutazone ionization kinetics.

Phenylbutazone has been associated with bioavailability problems and has shown nonclassical behavior in phase-transport studies. This nonclassical behavior has been attributed, in part, to the fact that phenylbutazone, as a carbon acid, undergoes noninstantaneous ionization kinetics. Instantaneous reaction is an assumption made in many diffusion-limited transport models involving a simultaneous ionization reaction. The ionization kinetics of phenylbutazone were determined at an ionic strength of 0.1 and 25 degrees using a stopped-flow spectrophotometer. A log kobs versus pH profile for the approach to the ionization equilibrium was determined, and a mechanism consistent with the profile was postulated. The percent enol versus the diketo form of phenylbutazone acid as well as pKaenol and pKadiketo was kinetically calculated. The protonation reaction was highly catalyzed by general acids while the deprotonation reaction was highly catalyzed by general bases. The general acid, water, was a poor proton donor to the anionic form (the so-called mesomericanion) of phenylbutazone.

Buffers↗
PubMed1979

Kinetics and mechanism of ionization of the carbon acids 4'-substituted 2-phenyl-1,3-indandiones.

The ionization kinetics of 1.3-diketone carbon acids are slow relative to those of classical acids and bases. The ionization kinetics of three 4'-substituted 2-phenyl-1,3-indandiones, 4'-chloro-, 4'-methoxy-, and 2-phenyl-1,3-indandione itself, were studied at 25 degrees and ionic strength 0.1 using stopped-flow spectrometry and a pH jump technique. A log k'obs-pH profile for the approach to the ionization equilibrium was consistent with a reaction scheme postulated earlier for the ionization of another carbon acid, phenylbutazone. The percent enol versus diketo form of the acids and the pKaenol and pKadiketo were calculated from the kinetic data. Hammett plots of the various kinetic and equilibrium constants supported a mechanism for acid deprotonation consistent with proton abstraction being the predominant process when very weak bases such as water were the proton acceptors. Desolvation effects and the work required to get the two reacting molecules together in the correct configurations predominated when the proton abstraction was by stronger proton acceptors.

Chemical Phenomena↗
PubMed1982

Measurements of ionization constants and partition coefficients of quanazole prodrugs.

A series of guanazole prodrugs, which are less water soluble than the parent compound and have relatively higher molecular weights, was recently synthesized, and their antineoplastic activities were measured in vitro. In present work, the ionization constants and partition coefficients of these compounds were measured for the first time. In contrast to guanazole, which is a weak base, guanazole prodrugs have been shown to be weak to moderate acids due to the electronic effects of the acyl group and the heterocyclic ring. Possible tautomeric and resonance structures are presented to account for the pKa values observed. Both the inductive and resonance effects of the substituent are important in determining the values of the ionization constant. The preparation of the prodrugs not only altered the lipophilicity but also drastically changed the acid-base property of the parent compound. The observed true partition coefficient values in most guanazole prodrugs studied were higher than those calculated from the pi-constants. Under highly ionized conditions, the small amount of water in the octanol layer has a significant effect in trapping a substantial amount of the ionized species in the octanol layer and gives rise to a higher log P value than expected. Under nonionized conditions, intramolecular hydrogen bonding plays an important factor in electron delocalization and reduction of hydrogen bonding with water molecules, causing the nonionized species of the guanazole prodrugs to be more lipophilic than expected.

Chemical Phenomena↗
PubMed2003

Cluster chemical ionization for improved confidence level in sample identification by gas chromatography/mass spectrometry.

Upon the supersonic expansion of helium mixed with vapor from an organic solvent (e.g. methanol), various clusters of the solvent with the sample molecules can be formed. As a result of 70 eV electron ionization of these clusters, cluster chemical ionization (cluster CI) mass spectra are obtained. These spectra are characterized by the combination of EI mass spectra of vibrationally cold molecules in the supersonic molecular beam (cold EI) with CI-like appearance of abundant protonated molecules, together with satellite peaks corresponding to protonated or non-protonated clusters of sample compounds with 1-3 solvent molecules. Like CI, cluster CI preferably occurs for polar compounds with high proton affinity. However, in contrast to conventional CI, for non-polar compounds or those with reduced proton affinity the cluster CI mass spectrum converges to that of cold EI. The appearance of a protonated molecule and its solvent cluster peaks, plus the lack of protonation and cluster satellites for prominent EI fragments, enable the unambiguous identification of the molecular ion. In turn, the insertion of the proper molecular ion into the NIST library search of the cold EI mass spectra eliminates those candidates with incorrect molecular mass and thus significantly increases the confidence level in sample identification. Furthermore, molecular mass identification is of prime importance for the analysis of unknown compounds that are absent in the library. Examples are given with emphasis on the cluster CI analysis of carbamate pesticides, high explosives and unknown samples, to demonstrate the usefulness of Supersonic GC/MS (GC/MS with supersonic molecular beam) in the analysis of these thermally labile compounds. Cluster CI is shown to be a practical ionization method, due to its ease-of-use and fast instrumental conversion between EI and cluster CI, which involves the opening of only one valve located at the make-up gas path. The ease-of-use of cluster CI is analogous to that of liquid CI in ion traps with internal ionization, and is in marked contrast to that of CI with most other standard GC/MS systems that require a change of the ion source.

Journal Article↗
PubMed1989

Microdetermination of glucose content of plasma and its isotopic enrichment using capillary gas chromatography/ammonia chemical-ionization mass spectrometry.

A new sensitive and precise method for the determination of the isotopic enrichment of [6,6-D2]glucose and concentration of glucose in plasma microsamples (20 microL) has been developed. Glucose was extracted from plasma samples by anion-cation column-exchange with absolute ethanol, derivatized as 1,2:3,5-bis(butylboronate)-6-acetyl-alpha-D-glucofuranose, and analysed by capillary gas chromatography/ammonia chemical-ionization mass spectrometry. This method gives a better reproducibility and precision (variation coefficient below 1%) than methods using isobutane chemical ionization. Stable isotopes are being used increasingly to investigate energy metabolism in vivo. Recent work has involved the development of methodologies, especially mass spectrometry, to perform tracer experiments using the stable isotopes 3H, 13C, or 13N(1-4). Chemical-ionization mass spectrometry is extensively used for the analysis of isotopically labelled amino acids. In neonates and children, "true" glucose production can be measured by the continuous infusion of the stable isotopically labelled tracer 6,6-dideutero-glucose (6,6-D2-glucose), and analytical measurement is performed using gas chromatography/electron-ionization mass spectrometry (GC/EIMS). Herein, we present a new, simple and sensitive method for the determination of the isotopic enrichment of [6,6-D2]glucose and measurement of the concentration of glucose in plasma microsamples (20 microL), based on the use of capillary gas-chromatography/ammonia chemical-ionization mass spectrometry of 1,2:3,5-bis(butylboronate)-6-acetyl-alpha-D-glucofuranose.

Blood Glucose↗
PubMed1992

Improvements in ion-trap chemical-ionization performance.

Ion-trap chemical-ionization performance has been improved by application of a modified scan function for the rejection of the undesired electron-ionization-like (EI-like) ions formed at the beginning of the reaction ionization period. The net effect of this software modification to the automatic reaction control is to produce chemical ionization (CI) spectra that are no longer adulterated with concentration-dependent EI-like ions. Under such improved conditions, CI spectra from an ion trap can now be directly compared with CI spectra produced on conventional quadrupole and magnet-scanning instruments.

Ions↗
PubMed2005

Gas-phase positive ion chemistry of 1-bromo-1-chloro-2,2,2-trifluoroethane (halothane) upon electron ionization within an ion trap mass spectrometer.

The positive ion chemistry occurring within an ion trap mass spectrometer upon electron ionization of 1-bromo-1-chloro-2,2,2-trifluoroethane, the important anaesthetic halothane, has been mapped by means of collision-induced decomposition and ion/molecule self-reaction experiments. Ionized halothane (M+*) reacts with neutral halothane to form the ionized olefin [ClBrC=CF2]+*. via HF elimination. Among the ionic fragments, [M-Br]+ and [M-F]+ react with halothane via chloride abstraction while [M-Cl]+ is unreactive under the same experimental conditions. Substituted methyl cations CHFX+ and CF2X+ (X = F, Cl, Br) undergo halide transfer processes, their reactivity being highest for X = F. Ionized carbenes CXY+ (X,Y = F,F; H,Br; H,Cl; H,F) react with halothane to form CClXY+ and CBrXY+, whereas CF+ inserts into the C-Cl bond to form CF3+ and CClF2+. Finally, Br+ and Cl+ react with halothane by charge transfer. Collision-induced dissociation experiments disclosed interesting rearrangements involved in the dissociations of +CHX-CF3 ions (X = Br, Cl), which undergo fluorine migration and elimination of CF2, as already observed for +CCl2-CF3 in a previous investigation.

Journal Article↗
PubMed2006

Desorption sonic spray ionization for (high) voltage-free ambient mass spectrometry.

Sonic spray ionization is shown to create a supersonic cloud of charged droplets able to promote efficient desorption and ionization of drugs directly from the surfaces of commercial drug tablets at ambient conditions. Compared with desorption electrospray ionization (DESI), desorption sonic spray ionization (DeSSI) is advantageous since it uses neither heating nor high voltages at the spray capillary. DeSSI therefore provides a more friendly environment in which to perform ambient mass spectrometry (MS). DeSSI-MS is herein evaluated for the analysis of drug tablets, and found to be, in general, as sensitive as DESI-MS. The (high) voltage-free DeSSI method provides, however, cleaner mass spectra with less abundant solvent cluster ions and with enough abundant analyte signal for tandem mass spectrometry (MS/MS). These features may therefore facilitate the DeSSI-MS detection of low molar mass components or impurities, or both. The higher-velocity supersonic DeSSI spray also facilitates matrix penetration thus providing more homogenous sampling and longer lasting ion signals.

Journal Article↗
PubMed1995

Facile, in situ matrix-assisted laser desorption ionization-mass spectrometry analysis and assignment of disulfide pairings in heteropeptide molecules.

During a routine analysis of disulfide-linked synthetic heterodipeptides by matrix-assisted laser desorption ionization (MALDI) mass spectrometry with linear detection we observed not only the expected mass of the dipeptide, but also the mass of the individual constituent monomer peptides. This was surprising because the peptide was purified as an intact dipeptide and no overt attempt was made to reduce the disulfide linkage before mass analysis. In contrast, analysis of the same sample by electrospray ionization mass spectrometry gave the mass of the dipeptide only. To investigate this further, two additional model heterodipeptides were prepared and all three were used to systematically study several matrix-assisted laser desorption ionization mass spectrometry parameters. These parameters were three different matrices (alpha-cyano-4-hydroxycinnamic acid, 2,5-dihydroxybenzoic acid, and sinapinic acid), both positive and negative modes of detection, and varying the acceleration voltage from 5 to 20 kV. Except for the sinapinic acid matrix where poor-quality spectra were obtained, all three model heterodipeptides fragmented under the tested conditions in a manner consistent with the cleavage of disulfide bonds, although the absolute level was sample dependent. The precise mechanism of disulfide cleavage during analysis is unknown, but the cleavage we observed appears to originate during the initial ionization event. Because the MALDI process involves irradiating samples with a laser, the fragmentation of disulfide-linked peptides that we observe bears some resemblance to light-induced homolytic cleavage of aqueous solutions of the amino acid cystine, although other mechanisms for fragmentation are also possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Observation of holoprotein molecular ions of several ferredoxins by electrospray-ionization-mass spectrometry.

Several ferredoxins containing [4Fe-4S] or [2Fe-2S] active sites have been analyzed by electrospray-ionization-mass spectrometry. For these acidic proteins, low pH conditions must be implemented in order to ensure strong signals in positive-ionization mode. Under such conditions the iron-sulfur active sites were lost in most cases. In contrast, the holoproteins were preserved under negative-ionization mode conditions: they were weakly but sufficiently ionized and information about their cofactor content could be obtained. The experimental conditions set up here should provide a useful basis for the detailed characterization of more complex iron-sulfur proteins.

Ferredoxins↗
PubMed1993

Identification of ionizable groups essential for the enzyme catalysis on glutathione S-transferase P.

The pH-Vmax/KmGSH plot of glutathione S-transferase P (GST-P) showed a bell-shaped profile, indicating bifunctional catalysis for glutathione (GSH) conjugation. The ionization constant (Ke) and the heat of ionization (delta He) of the essential ionizable group in the GSH binding site were measured and the value of pKe1 was 5.9 and that of pKe2, 8.4, while the delta He1 and delta He2 were -0.2 and 7.9 kcal/mole, respectively. In a solvent containing 25% ethanol, pKe1 and pKe2 shifted to the alkaline side by 0.47 and 0.2, respectively. These kinetic results indicated that carboxyl and phenolic groups were ionizable groups essential for the GSH conjugation. Chemical modifications using aminomethane sulfonic acid and N-acetylimidazole supported the results of the kinetic studies.

Animals↗
PubMed1998

ZK1, a novel Krüppel-type zinc finger gene, is induced following exposure to ionizing radiation and enhances apoptotic cell death on hematopoietic cells.

To identify and early response factor by exposure to ionizing radiation, we cloned the cDNA of a novel Krüppel-type zinc finger (ZNF) gene, ZK1, from a cDNA library constructed from the human leukemia cell line, CMK86, using degenerate primers. This cDNA encoded a protein of 671 amino acids with an A box of Krüppel-associated box (KRAB) domain at the N-terminus, followed by 15 ZNF motifs. The expression level of the ZK1 mRNA in human leukemia cells lines, CMK86 and U937, was increased after exposure to ionizing radiation. Furthermore, murine myeloid precursor 32D cells that were stably transfected with ZK1 cDNA had higher sensitivity to ionizing radiation than the 32D parent cells. These data suggest that the ZK1 gene is one of early response genes by exposure to ionizing radiation, and may have some functions on radiation-induced apoptotic cell death on hematopoietic cells.

Amino Acid Sequence↗
PubMed1996

Coupling between folding and ionization equilibria: effects of pH on the conformational preferences of polypeptides.

A new approach to the conformational study of polypeptides is presented. It considers explicitly the coupling between the conformation of the molecule and the ionization equilibria at a given pH value. Calculations of the solvation free energy and free energy of ionization of a 17-residue polypeptide are carried out using a fast multigrid boundary element method (MBE). The MBE method uses an adaptive tessellation of the molecular surface by boundary elements with non-regular size to solve the Poisson equation rapidly, and with a high degree of accuracy. The MBE method is integrated into the ECEPP (Empirical Conformational Energy Program for Peptides) algorithm to compute the coupling between the ionization state and the conformation of the molecule. This approach has been applied to study the conformational preference of a short polypeptide for which the available NMR and CD experimental data indicate that conformations containing a right-handed alpha-helical segment are energetically more favorable at low values of pH. The results of calculations using the present method agree quite well with experiments, in contrast to previous applications with standard techniques (using pre-assigned charges at each pH) that were not able to reproduce the experimental findings. Also, it is shown how the coupling to the conformation leads to different degrees of ionization of a given type of residue, for example glutamic acid, at different positions in the amino acid sequence, at any given pH. The results of this study provide a sound basis to discuss the origin of the stability of polypeptide conformations, and its dependence on the environmental conditions.

Computer Simulation↗
PubMed1990

The crosslinking of nuclear protein to DNA using ionizing radiation.

DNA-protein complexes were generated in intact Chinese hamster ovary (CHO) cells by the use of ionizing radiation. The DNA-protein crosslinks, as measured by a filter-binding assay, occurred immediately following the irradiation, were produced in a dose-dependent manner and were reversible. The reversibility of the crosslinks in the intact cells was dependent upon general protein synthesis. Three proteins that were attached to DNA in unirradiated cells were analyzed according to the presence of DNA attached to the proteins before, during and after exposure to ionizing radiation. All three proteins contained more DNA reversibly attached to the proteins after exposure to 5 Gy ionizing radiation as compared to unirradiated cells. One of the proteins was increasingly attached to DNA using 2.5-50 Gy X-ray. These data suggest that the increased DNA-protein crosslinking observed with ionizing radiation may involve the increase in particular protein(s) crosslinked to DNA as well as an increase in the amount of DNA attached to specific proteins.

Antibodies, Monoclonal↗
PubMed1994

Apoptosis occurs in lymphoma cells but not in hepatoma cells following ionizing radiation and photodynamic therapy.

The aim of this study was to determine the relative role of apoptosis in photodynamically-induced cytotoxicity or radiation-induced cytotoxicity for hepatoma and lymphoma cells. Human hepatoma cells and mouse lymphoma cells were treated with either photodynamic therapy (PDT) or ionizing radiation. Dosimetry studies of immediate cell death following photodynamic therapy in the hepatoma cell line demonstrated second-order kinetics, similar to that seen in the lymphoma cells. No immediate cell death was noted in the hepatoma or lymphoma cells following ionizing radiation, but experiments measuring delayed cell death demonstrated a dose-dependent response. Maximum DNA ladder formation occurred 2 hr after PDT and 24 hr after ionizing radiation in the lymphoma cells, which was consistent with the time courses of cell death for these treatments. The hepatoma cell line did not demonstrate DNA ladder formation despite dosages of PDT or ionizing radiation sufficient to cause high levels of cytotoxicity.

Animals↗
PubMed1985

Ionized calcium measurement in vitro: is it necessary?

Experimental data obtained from a study on the inhibition of placental Ca-ATPase by ethacrynic acid were graphically analyzed using either total calcium or ionized calcium as the independent variable. Correct interpretation of the results required actual measurement of ionized calcium in the incubation medium. The assumption that ionized calcium is equal to the total calcium resulted in artifacts and led to erroneous conclusions. These observations emphasize the necessity for accurate measurement of ionized calcium in test systems where calcium effects are being examined.

Animals↗