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PubMed2005

Vapor pressure and intramolecular hydrogen bonding in fluorotelomer alcohols.

Vapor pressure and aqueous solubility are important parameters used to estimate the potential for transport of chemical substances in the atmosphere. For fluorotelomer alcohols (FTOHs), currently under scrutiny by environmental scientists as potential precursors of persistent perfluorocarboxylates (PFCAs), vapor pressure is the more significant property since these compounds are only very sparingly soluble in water. We have measured the vapor pressures of a homologous series of fluorotelomer alcohols, F(CF2CF2)nCH2CH2OH (n = 2-5), in the temperature range 21-250 degrees C by three independent methods: (a) a method suitable for very low vapor pressures at ambient temperatures (gas-saturation method), (b) an improved boiling point method at controlled pressures (Scott method), and (c) a novel method, requiring milligram quantities of substance, based on gas-phase NMR, a technique largely unfamiliar to chemists and holding promise for studies of relevance to environmental chemistry. The concordant values obtained indicate that recently published vapor pressure data overestimate the vapor pressure at ambient temperature, and therefore the volatility, of this series of fluorinated compounds. It was suggested that substantial intramolecular -O-H...F- hydrogen bonding between the hydroxylic proton and the two fluorines next to the ethanol moiety was responsible for their putative high volatility. Therefore, we have used gas-phase NMR, gas-phase FTIR, 2D NMR heteronuclear Overhauser effect measurements, and high-level ab initio computations to investigate the intramolecular hydrogen bonding in fluorotelomer alcohols. Our studies unequivocally show that hydrogen bonding of this type is not significant and cannot contribute to and cause unusual volatility. The substantially lower vapor pressure at ambient temperatures than previously reported resulting from our work is important in developing a valid understanding of the environmental transport behavior of this class of compounds.

Journal Article↗
PubMedDate not supplied

Novel non-invasive probes for measuring tumor-hypoxia by 19F-magnetic resonance spectroscopy (19F-MRS). Studies in the SCCVII/C3H murine model.

BACKGROUND: 19F-labeled 2-nitroimidazoles bound to hypoxic cells in tumors are known to be useful probes for measuring hypoxia since they can allow for their non-invasive detection by 19F nuclear magnetic resonance, provided that they do not lose 19F during their hypoxia-mediated metabolism. Two such compounds, N-(m-trifluoromethylbenzyl)-3-(2-nitro-1-imidazolyl)-propylamine hydrochloride (mTFN-1) and 5,6-dimethyl-4-[3-(2-nitro-1-imidazolyl)-propylamino]-2-trifluoromethylpyrimidine hydrochloride (CF3PM) were selected from a series of analogs, for their in vivo evaluation, based on their high solubility in saline and low toxicity in mice. MATERIALS AND METHODS: MRS experiments were performed in anesthetized C3H mice bearing SCCVII tumors in their flanks. Fluorinated compounds, mTFN-1 or CF3PM, were injected intraperitoneally (i.p.) at a dose of 110 or 150 mg/kg, respectively, in 0.75 mL saline. A 0.9 cm surface coil tuned to fluorine frequency was positioned directly over the tumor, the head, or the liver and 1800 transients were collected over 20 min in a Bruker Omega 4.7 T instrument. Spectroscopic measurements were taken at 2, 7 and 19 h post injection of the fluorinated drug. RESULTS: CF3PM was detected in the plasma up to 2 h post injection with maximum concentration observed 30 min post administration. In the MRS studies, mTFN-1 signal in the tumor was 68.8, 86.8 and 27.2% of the reference at 1-2, 6-7 and 18-19 h post injection, respectively. The corresponding values in the brain were 0, 125.7 and 26.6%, respectively, whereas the corresponding values in the liver were 359.3, 307.7 and 0%, respectively. CF3PM signal in the tumor was 3.3, 57.7 and 7.1% of the reference at 1-2, 6-7 and 18-19 h post injection, respectively. The corresponding values in the liver were 267.6, 60.5 and 0%, respectively. No CF3PM signal was detected in the brain at any time interval. CONCLUSION: These results suggest that CF3PM could be used as a potential probe for measuring hypoxia in tumors by 19F-MRS.

Animals↗
PubMed2006

Emission factors of air toxics from semiconductor manufacturing in Korea.

The development of local, accurate emission factors is very important for the estimation of reliable national emissions and air quality management. For that, this study is performed for pollutants released to the atmosphere with source-specific emission tests from the semiconductor manufacturing industry. The semiconductor manufacturing industry is one of the major sources of air toxics or hazardous air pollutants (HAPs); thus, understanding the emission characteristics of the emission source is a very important factor in the development of a control strategy. However, in Korea, there is a general lack of information available on air emissions from the semiconductor industry. The major emission sources of air toxics examined from the semiconductor manufacturing industry were wet chemical stations, coating applications, gaseous operations, photolithography, and miscellaneous devices in the wafer fabrication and semiconductor packaging processes. In this study, analyses of emission characteristics, and the estimations of emission data and factors for air toxics, such as acids, bases, heavy metals, and volatile organic compounds from the semiconductor manufacturing process have been performed. The concentration of hydrogen chloride from the packaging process was the highest among all of the processes. In addition, the emission factor of total volatile organic compounds (TVOCs) for the packaging process was higher than that of the wafer fabrication process. Emission factors estimated in this study were compared with those of Taiwan for evaluation, and they were found to be of similar level in the case of TVOCs and fluorine compounds.

Air Pollutants↗
PubMed2001

Antitumor benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles.

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substituted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioisomeric 5- and 7-fluoro-benzothiazoles were formed from the established Jacobsen cyclization of precursor 3-fluoro-thiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these target compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently cytotoxic (GI(50) < 1 nM) in vitro in sensitive human breast MCF-7 (ER+) and MDA 468 (ER-) cell lines but inactive (GI(50) > 10 microM) against PC 3 prostate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dose-response relationship characteristically shown by the benzothiazole series against sensitive cell lines was exhibited by the 4- and 6-fluoro-benzothiazoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The most potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h) which, unlike the 6-fluoro isomer (10d), produces no exportable metabolites in the presence of sensitive MCF-7 cells. Induction of cytochrome P450 CYP1A1, a crucial event in determining the antitumor specificity of this series of benzothiazoles, was not compromised. 10h is currently the focus of pharmaceutical and preclinical development.

Antineoplastic Agents↗
PubMed2002

The role of surface free energy on the formation of hybrid bilayer membranes.

The interaction of small phospholipid vesicles with well-characterized surfaces has been studied to assess the effect of the surface free energy of the underlying monolayer on the formation of phospholipid/alkanethiol hybrid bilayer membranes (HBMs). The surface free energy was changed in a systematic manner using single-component alkanethiol monolayers and monolayers of binary mixtures of thiols. The binary surfaces were prepared on gold by self-assembly from binary solutions of the thiols HS-(CH(2))(n)()-X (n = 11, X = CH(3) or OH) in THF. Surface plasmon resonance (SPR), electrical capacitance, and atomic force microscopy (AFM) measurements were used to characterize the interaction of palmitoyl,oleoyl-phosphatidylcholine (POPC) vesicles with the surfaces. For all surfaces examined, it appears that the polar part of surface energy influences the nature of the POPC assembly that associates with the surface. Comparison of optical, capacitance, and AFM data suggests that vesicles can remain intact or partially intact even at surfaces with a contact angle with water of close to 100 degrees. In addition, comparison of the alkanethiols of different chain lengths and the fluorinated compound HS-(CH(2))(2)-(CF(2))(8)-CF(3) that characterize with a low value of the polar part of the surface energy suggests that the quality of the underlying monolayer in terms of number of defects has a significant influence on the packing density of the resulting HBM layer.

Adsorption↗
PubMed2000

Stability of commercial solutions of 5-fluorouracil for continuous infusion in an ambulatory pump.

PURPOSE: The stability of 5-fluorouracil (FU) Roche solutions in a portable infusion pump under prolonged "in-use" conditions (32 degrees C, in the dark) was studied, especially with respect to the formation of the cardiotoxic compounds fluoroacetaldehyde (Facet) and fluoromalonic acid semialdehyde (FMASAld). METHODS: The solutions, prepared according to three protocols frequently used at the Anticancer Centre in Toulouse, were analysed by 19F NMR immediately after preparation (T0) and after 2, 3 or 10 days (TF) in the pump. RESULTS: The commercial solution already contained 64 fluorinated "impurities", among them fluoride ion (F-), FMASAld and Facet. The concentration of FU did not change significantly between T0 and TF, whatever the protocol. The levels of F- had not increased significantly after 2 or 3 days, but had increased by about 50% after 10 days. The increases in FMASAld levels were low (12-28%) albeit significant in the three protocols. The levels of Facet had increased by a factor of about 2 after 2 or 3 days, and by a factor of > 3 after 10 days. The levels of the other fluorinated compounds were constant during the first 2 or 3 days, but had increased by about 30% after 10 days. FU Dakota lyophilizates, analysed immediately after reconstitution, contained neither FMASAld nor Facet. After 2 days at 25 degrees C, low levels of FMASAld were present but Facet could still not be detected. CONCLUSION: This study showed that special attention must be paid to the risk of increasing concentrations of highly toxic FMASAld and Facet when FU is administered via a pump for long periods of time. It would be preferable not to exceed 3 days of treatment when patients receive FU from a portable infusion pump. This underlines the interest in using a lyophilized formulation of FU in clinical practice.

Antimetabolites, Antineoplastic↗
PubMed2004

Packing conflicts in the Z' = 5 structure of CF(3)(CF(2))(3)(CH(2))(10)COOH.

Dimers of the partially fluorinated amphiphile 1-(perfluorobutyl)undecanoic acid, CF(3)(CF(2))(3)(CH(2))(10)COOH, crystallize in the same basic packing arrangement found for many n-alkyl carboxylic acids. The unit cell of the fluorinated compound, however, contains five independent molecules rather than the one found for most n-alkyl carboxylic acids including CH(3)(CH(2))(13)COOH. The structures of the two C(15) acids are compared. The structural modulations that lead to the large value of Z' can be understood as resulting from the conflict between the necessity of filling space densely and uniformly and the tendency of unlike groups to be segregated spatially. The few other known structures of compounds with both (CF(2))(n) and (CH(2))(m) regions show evidence of the same conflict.

Crystallization↗
PubMed1993

New fluorinated dopamine D2 ligands with benzofuran skeleton. The synthesis and in vitro evaluation.

New fluorinated ligands with N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,3-dihydrobenzofuran-7-carboxamide skeleton, which are useful as a prototype to develop 18F labelled in vivo radiotracer for positron emission tomography (PET), were synthesized, and their binding affinities for the dopamine D2 receptors were investigated. Fluorine atom was introduced at C-4 of the pyrrolidine ring (10) or at ethyl substituent at C-5 of the dihydrobenzofuran moiety (20). The in vitro IC50 values of these ligands for the dopamine D2 receptors which were determined by their ability to inhibit the binding of [3H]spiperone binding in rat striatal membrane were 17 and 36 nM, respectively. Thus, the fluorinated compounds 10 and 20 may be possible candidates for further in vivo investigation.

Animals↗
PubMed1990

Synthesis and antiproliferative activity of threo-5-fluoro-L-dihydroorotate.

Fluorinated compounds play an important role in enzymology as well as clinical medicine. Based on the stereochemical preferences of dihydroorotate oxidase and enzymes that use fluoroaspartate, it was anticipated that threo-5-fluoro-L-dihydroorotate (t-FDHO) would have the properties of an antimetabolite. Thus, t-FDHO was synthesized via the reduction of 5-fluoroorotate using NADH and dihydroorotate dehydrogenase that was free of dihydroorotase. When the product was purified and studied by high field proton and carbon 13 NMR, the fluorine, the five carbons, and all the nonexchangeable protons were readily observed. Confirmation of threo configuration was obtained by examining the vicinal coupling constants between the substituents on carbon 5 and carbon 6 of the newly synthesized compound. Additionally, t-FDHO could be reoxidized to 5-fluoroorotate in the presence of dihydroorotate dehydrogenase and NAD+. Treatment of t-FDHO with dihydroorotase generated N-carbamyl-threo-3-fluoro-L-aspartate (CTF-ASP) which was also purified and characterized by NMR. The antiproliferative activity of t-FDHO was determined against a diploid human fibrosarcoma cell line (HT-1080). Fifty microM t-FDHO caused 50% inhibition of HT-1080 cell proliferation. During the 48-h toxicity study, extracellular t-FDHO underwent significant hydrolysis to CTF-ASP. Further extracellular degradation to fluoroaspartate was not seen. The antiproliferative activity of t-FDHO was not due to extracellular degradation since CTF-ASP itself was essentially nontoxic.

Antineoplastic Agents↗
PubMedDate not supplied

Reaction characteristics of a tooth-bleaching agent containing H2O2 and NaF: in vitro study of crystal structure change in treated hydroxyapatite and chemical states of incorporated fluorine.

This in vitro study was performed to elucidate the reaction mechanism of sodium fluoride (NaF), which is added to tooth-bleaching agents to lessen the adverse effect of hydrogen peroxide (H2O2) on teeth. Both hydroxyapatite (HAP) and dihydrated dicalcium phosphate (DCPD), model substances for dental hard tissues, dissolved easily in a simple H2O2 solution. In the H2O2/NaF solutions, however, fluorine compounds that could not be identified by X-ray diffraction (XRD) due to the smallness of the products were formed on the surface of the HAP. X-ray photoelectron spectroscopy (XPS) studies demonstrated that fluoridated hydroxyapatite (FHAP) was formed on HAP, and that calcium fluoride (CaF2) formation was accelerated by increasing the concentrations of fluorine and H2O2 along with the partial dissolution of HAP. In H2O2/NaF solution, DCPD also transformed easily to FHAP and CaF2, which are favorable to the remineralization process on the tooth surface. Thus, the mechanism of NaF was elucidated, and its use together with H2O2 for tooth bleaching was proved to be effective. Methodologically, the XPS two-dimensional plot made it possible for the first time to directly estimate the ratio of FHAP and CaF2 in the reaction products, in contrast to the conventional wet-analytical method, which is simply based on the difference in solubility of the two components.

Crystallization↗
PubMed2004

Use of 19F NMR spectroscopy to screen chemical libraries for ligands that bind to proteins.

Identification of compounds from chemical libraries that bind to macromolecules by use of NMR spectroscopy has gained increasing importance during recent years. A simple methodology based on (19)F NMR spectroscopy for the screening of ligands that bind to proteins, which also provides qualitative information about relative binding strengths and the presence of multiple binding sites, is presented here. A library of fluorinated compounds was assembled and investigated for binding to the two bacterial chaperones PapD and FimC, and also to human serum albumin (HSA). It was found that library members which are bound to a target protein could be identified directly from line broadening and/or induced chemical shifts in a single, one-dimensional (19)F NMR spectrum. The results obtained for binding to PapD using (19)F NMR spectroscopy agreed well with independent studies based on surface plasmon resonance, providing support for the versatility and accuracy of the technique. When the library was titrated to a solution of PapD chemical shift and linewidth changes were observed with increasing ligand concentration, which indicated the presence of several binding sites on PapD and enabled the assessment of relative binding strengths for the different ligands. Screening by (19)F NMR spectroscopy should thus be a valuable addition to existing NMR techniques for evaluation of chemical libraries in bioorganic and medicinal chemistry.

Bacterial Proteins↗
PubMed2004

New and efficient syntheses of alpha-iodo-alpha,alpha-difluoro- and beta-iodo-alpha,alpha,beta,beta-tetrafluorocarboxylic acid derivatives as useful building blocks for making functional fluoro compounds.

Perfluoroolefins reacted with I-Cl and ClSO(3)H under mild conditions to give R(F)CFICF(2)OSO(2)Cl, which could be readily converted into various alpha-iodo-perfluorocarboxylic acid derivatives or telomerized with tetrafluoroethylene to I(CF(2)CF(2))(n)()OSO(2)Cl. Ring-opening reaction of perfluoroalkoxypentafluorocyclopropane with iodine at 240 degrees C produced ICF(2)CF(2)COF, which was quenched by alcohol, water, or NH(3) to give beta-iodo-alpha,alpha,beta,beta-tetrafluorocarboxylic acid derivatives. These functional fluorinated iodides can be used as building blocks for making selectively fluorinated compounds.

Journal Article↗
PubMed1986

Metabolic pathway of 2-deoxy-2-fluoro-D-glucose studied by F-19 NMR.

The behavior of 2-deoxy-2-fluoro-D-glucose (FDG) in mouse has been studied by F-19 NMR method for long period. The F-19 NMR signals of FDG or its metabolites were observed in tissues without serious broadening. FDG was found to be accumulated in organs in the form of FDG or FDG-6-phosphate and 2-deoxy-2-fluoro-D-mannose (FDM) or FDM-6-phosphate, and the latter dominated the former in the heart sampled at 24 hr or later. The fluorine compounds were excreted in urine in both forms. The clearance was rapid from brain, liver, and blood, but was slow from heart.

Animals↗
PubMed1992

Percutaneous absorption of flurbiprofen in the hairless rat measured in vivo using 19F magnetic resonance spectroscopy.

The objective of this investigation was to develop a new methodology using 19F-magnetic resonance spectroscopy (MRS) to measure the in vivo percutaneous absorption of flurbiprofen through hairless rat skin. A 2% W/V flurbiprofen gel (Klucel HF, hydroxypropyl cellulose 1.5% to 2% W/V) containing isopropyl alcohol, water, and propylene glycol (55:35:10 v/v/v) was prepared. A 2-mg dose (100 mg of gel) was applied to the skin of the lower back of an anesthetized hairless rat, contained with a rubber o-ring, and occluded with a lexan plastic cover slip. The animal was placed on an MR surface coil (3.5-cm diameter tuned to 19F) and measurements taken continuously over approximately 3 h in 10-min intervals with a 2-tesla GE CSI nuclear magnetic resonance (NMR) spectrometer. One measures the disappearance of MR signal intensity per interval, which directly relates to the percent of drug disappearance over time, which in turn was converted to a flux value. The flux of flurbiprofen in vivo was found to be 95 +/- 22 micrograms/cm2/h. This is approximately four times greater than the flux of flurbiprofen through excised human skin reported by Akhter and Barry (22 +/- 14 micrograms/cm2/h). This new in vivo method measures drug disappearance and can be readily transferred to man. This method may be adapted to study other fluorine compounds or other nuclei with magnetic properties. It avoids exposure of a patient or animal to the radiation used in x-ray fluorescence methods or to 14C- or 3H-radiolabeled drugs.

Animals↗
PubMed1997

Comparative tolerability profiles of the inhaled anaesthetics.

Improved understanding of the structure/activity relationship of inhaled anaesthetics has resulted in the synthesis of fluorinated compounds which are more potent and less toxic than their unfluorinated antecedents. The toxic effects of inhaled anaesthetics on the liver and kidney are complex but, in general, are related to the extent to which individual inhaled agents are metabolised. Halothane hepatotoxicity is a rare, idiosyncratic reaction which typically occurs in obese women having more than one exposure to the drug within a short time interval. All currently available volatile anaesthetic drugs have depressant effects on the cardiovascular and respiratory systems; arrhythmias are more likely with halothane than with the fluorinated ethers. Cerebral blood flow tends to increase during inhalation anaesthesia, especially with halothane and in the presence of hypercarbia; isoflurane may be given sparingly during neurosurgical procedures whilst monitoring its end-tidal concentration. Although the volatile agents tend to cause uterine relaxation they may be given safely in low concentration to avoid awareness during Caesarean section. In general, young children require rather higher concentrations of volatile agents than adults and seem to be less susceptible to organ toxicity. Two relatively new volatile agents, sevoflurane and desflurane, offer some advantages over isoflurane but neither is an "ideal drug'. Sevoflurane interacts with soda-lime to produce a series of degradation products, the most important of which is compound A. Production is greatest during low-flow, closed circuit anaesthesia using high inspired concentrations of the drug. Compound A has nephrotoxic potential in rats but the clinical significance of the interaction between sevoflurane and soda-lime is unclear. Nitrous oxide when given for prolonged periods may cause irreversible bone marrow depression.

Anesthetics, Inhalation↗
PubMed2001

Electrolytic partial fluorination of organic compounds. 55. Highly regio- and stereoselective anodic monofluorination of 2,3-dihydrochroman-4-one and chromone derivatives.

Anodic monofluorination at the position alpha to the oxygen atom of the (E)-3-benzylidene-2,3-dihydrochroman-4-one derivatives was successfully carried out to provide the corresponding 2-fluorochromanones selectively. This is the first regioselective electrochemical fluorination of fused-type, oxygen-containing heterocyclic compounds. Anodic fluorination of a chromone derivative also gave a similar fluorinated chromanone stereoselectively.

Journal Article↗
PubMed2000

Mass spectrometrically detected directly coupled high performance liquid chromatography/nuclear magnetic resonance spectroscopy/mass spectrometry for the identification of xenobiotic metabolites in maize plants.

Reconstructed ion chromatograms have been used to identify relevant high performance liquid chromatography (HPLC) peaks in a directly coupled high performance liquid chromatography/nuclear magnetic resonance spectroscopy/mass spectrometry (HPLC/NMR/MS) experiment. This has been applied to a study of the metabolism of a model compound, 5-nitropyridone (2-hydroxy-5-nitropyridine), in maize plants grown hydroponically. By monitoring the on-flow reconstructed ion chromatogram corresponding to the 5-nitropyridone fragment at m/z 143, and additional molecular ions corresponding to metabolites identified as products from similar compounds, relevant peaks were identified rapidly for subsequent stopped-flow 1H NMR spectroscopic analysis. The combination of coupled HPLC/NMR/MS enabled the direct identification of three metabolites, namely the N-glucoside, N-malonylglucoside, and O-malonylglucoside. This work demonstrates the power of HPLC/NMR/MS for the structural elucidation of xenobiotic metabolites in complex biological matrices (such as plant material) with minimal sample preparation. In particular, using mass spectrometry for the initial identification of relevant HPLC peaks allows the analysis of complex samples without the necessity for other spectroscopic markers, such as 19F NMR signal for fluorinated compounds or UV spectroscopy for molecules with strong UV chromophores.

Chromatography, High Pressure Liquid↗
PubMed1991

19F nuclear magnetic resonance analysis of trifluoroethanol metabolites in the urine of the Sprague-Dawley rat.

2,2,2-Trifluoroethanol (TFE) is a common industrial solvent and a known metabolite of the inhalation anesthetics fluroxene (2,2,2-trifluoroethyl vinyl ether) and halothane (2-bromo-2-chloro-1,1,1-trifluoroethane). The water-soluble metabolites of TFE were identified in the urine of Sprague-Dawley rats using 19F NMR spectroscopy. In rats dosed with 0.21 g TFE/kg body weight, approximately one-half of the administered TFE was excreted as the trifluoroethyl glucuronide. The remaining TFE was oxidized, primarily to trifluoroacetaldehyde hydrate, with a small percentage of the aldehyde oxidized further to trifluoroacetate. One additional fluorinated compound was found; after investigation, this was identified as a Schiff's base compound resulting from the addition of trifluoroacetaldehyde to urea. The time-dependent excretion of TFE metabolites was measured as a function of ethanol induction of hepatic enzymes. This study demonstrates the utility of 19F NMR for the analysis of drug metabolism in laboratory animals. In addition, the resistance of trifluoroacetaldehyde hydrate to further oxidation, coupled with its reactivity with common cellular amines, indicates the potential toxicity of this metabolite to mammalian tissues.

Acetaldehyde↗