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PubMed1999

An efficient synthesis of a 4'-phosphonodifluoromethyl-3'-formyl-phenylalanine containing SRC SH2 ligand.

A CuBr-mediated, regioselective cross-coupling between methyl 2,5-diiodobenzoate (4) and [(diethoxyphosphinyl)difluoromethyl]zinc bromide is reported. Palladium-catalyzed incorporation of an amino acid side chain, followed by subsequent modifications resulted in the rapid construction of 2. Compound 2 was designed to engage Cys188 of the Src SH2 domain, however, this was not observed spectroscopically.

Binding Sites↗
PubMed1984

D,L-alpha-Fluoropalmitic acid inhibits sphingosine base formation and accumulates in membrane lipids of cultured mammalian cells.

D,L-alpha-Fluoropalmitic acid was synthesized by tosylation of methyl-D,L-alpha-hydroxypalmitate, and displacement of the tosylated function by tetrabutylammonium fluoride in acetonitrile. Uptake and utilization of the compound by cultured Balb/c 3T3 cells were studied after presentation of the fluoro fatty acid analogue complexed with bovine serum albumin. A concentration of 0.28 mM had very little effect on cell growth over several days of incubation, and cell morphology was unchanged. Chromatographic and mass spectrometric analyses at 6 and 12 h of incubation showed that D,L-alpha-fluoropalmitic acid was taken up by the cells and incorporated without modification as a fatty acyl moiety into select lipids. Significant levels of the compound were found at 12 h in phosphatidylcholine (1.6%) and sphingomyelin (0.6%) fatty acids, but not in those of other phospholipids or neutral lipids. D,L-alpha-Fluoropalmitic acid represented a significant percentage of the fatty acids of neutral glycosphingolipids (1.4%) and ceramides (0.8%) by 12 h. The fluoro fatty acid was not incorporated into long-chain sphingolipid bases, and mass spectrometry failed to reveal additional carbon-2 fluorine-substituted compounds in cellular lipids. Cellular levels of triacylglycerols and phosphatidylcholine remained essentially unchanged, or were slightly increased, while amounts of ceramide and gangliosides were decreased. Comparison of labeled palmitate incorporation into sphingolipid bases and fatty acids of sphingomyelin suggested inhibition of sphingosine synthesis by the fluoro fatty sphingomyelin suggested inhibition of sphingosine synthesis by the fluoro fatty acid. D,L-alpha-Fluoropalmitic acid inhibited the formation of palmitoyl-CoA by Balb/c 3T3 long-chain acyl-CoA synthetase in vitro. The results support involvement of CoA thiol ester-independent steps in modification of membrane lipids.

Animals↗
PubMed2001

Synthesis and antiparasitic activity of 2-(trifluoromethyl)-benzimidazole derivatives.

2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamnoeha histolytica. and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.

Animals↗
PubMed2002

Predicted distribution and ecological risk assessment of a "segregated" hydrofluorrother in the Japanese environment.

An assessment of HFE-7500, a 'segregated' hydrofluoroether, was conducted to evaluate the potential for exposure to and subsequent effects on humans and wildlife in Japan. The segregated hydrofluoroethers belong to a class of fluorochemicals currently being proposed as replacements for traditional fluorochemicals (CFCs and PFCs) that are currently being used in several industries, in particular, the semiconductor industry. These traditional compounds have been implicated as ozone-depleting or potent "greenhouse gases". The segregated hydrofluoroethers have useful physical and chemical properties, but do not contribute to ozone depletion and have lower "global warming potential" (GWP) indices. Although the physical properties of these materials (low H2O solubility and high vapor pressure) suggest there would be a very low level of risk to aquatic systems, a thorough analysis had not been previously performed. Predicted environmental concentrations (PECs) of HFE-7500 in Japan were determined with the Higashino model, a Gausian puff and plume model that used an approximation of environmental releases to the atmosphere as input to the model. Allowable concentrations to protect aquatic life, wildlife, and humans from noncancer effects were determined as detailed in USEPA's final Water Quality Guidance for the Great Lakes Systems. Potential risk to ecological receptors and humans was determined by calculating hazard quotients and margins of safety. The results of the risk assessment indicate that HFE-7500 poses no significant risk to either aquatic or terrestrial wildlife species or humans living in the Japanese environment. The least margin of safety for any ecological receptor was 100,000, and a margin of safety greater than 100,000,000 for most receptors indicated that HFE-7500 poses no threat to human health. Because of a scarcity of toxicity and exposure data, the risk assessment was based on very conservative assumptions. Therefore, the actual margins of safety for both humans and wildlife could have been 100- to 1,000-fold greater if additional data were available such that less stringent uncertainty factors could be applied. These results suggest that the environmental impact of HFE-7500 should be inconsequential based on the marked improvement in its atmospheric properties relative to the traditional compounds currently in use. Given the short atmospheric lifetime and low global warming potential of this material, its replacement of CFCs and PFCs would result in a net improvement of environmental health and safety.

Animals↗
PubMed2003

Structural studies of N,N'-di(ortho-fluorophenyl)formamidine group 1 metallation.

The treatment of N,N'-di(ortho-fluorophenyl)formamidine (HFPhF) in tetrahydrofuran with equimolar amounts of n-butyllithium, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide affords the colourless crystalline formamidinate complexes [Li(FPhF)(thf)] (1), [Na(FPhF)(thf)] (2) and [K(FPhF)] (5). Low-temperature preparation of 2 in diethyl ether yields the Et(2)O adduct [Na(FPhF)(Et(2)O)] (3). At ambient temperature the sodium fluoride inclusion complex [Na(3)(FPhF)(3)(Et(2)O)(NaF)] (4) is also formed. Spectroscopic ((1)H, (13)C and (19)F((1)H) NMR) data for 1-5, microanalytical analyses for compounds 1, 2 and 5 and X-ray structure determinations for 1, 3-5 confirm the formulae of these species. In the solid-state, 1 and 3 possess a dimeric nature in which the formamidinate ligands coordinate through mu(2):eta(2):eta(1) (1) and mu(2):eta(2):eta(2) (3) binding modes. These are enabled by partial ortho-fluoro donation. Compound 4, which is also dimeric, contains two trisodium tris(formamidinate) units that comprise mu(2):eta(2):eta(2)-FPhF ligands, a bridging diethyl ether moiety and an unprecedented mu(3):eta(2):eta(2):eta(2)-formamidinate donor. Together, these trinuclear units encapsulate two sodium fluoride units by eta(2)-N,N-formamidinate chelation of the sodium cations (thereby creating further mu(3):eta(2):eta(2):eta(2)-bound formamidinates) and fluoride-sodium interactions. Compound 5 extends the coordinative versatility of FPhF to mu(2):eta(4):eta(3) coordination by the generation of K(2)(mu(2):eta(4):eta(3)-FPhF)(2) units that exhibit eta(2)-arene interactions. Macromolecularly, the overlaying of these units affords a polymeric solvent-free structure that incites coordination of the FPhF ligands to metal atoms above and below the K(2)(FPhF)(2) plane. Overall, this generates a remarkable mu(4):eta(4):eta(3):eta(2):eta(1)-amidinate binding mode that incorporates both bridging and terminal fluorine donors. Compounds 1-5 are the first non-chromium complexes of N,N'-di(ortho-fluorophenyl)formamidinate.

Journal Article↗
PubMed2005

Characterization of monofluorinated polycyclic aromatic compounds by 1H, 13C and 19F NMR spectroscopy.

Monofluorinated polycyclic aromatic hydrocarbons (F-PAHs) have attracted much attention in analytical, environmental, toxicological and mechanistic studies because of their physico-chemical properties, which are closely similar to those of the parent PAHs. Because of this, full NMR characterization has become of interest. Complete 1H, 13C and 19F NMR chemical shifts, and also 1J(H,C), (n)J(C,F), (n)J(H,F) and (n)J(H,H) coupling constants, have been assigned for the F-PAHs 1-fluoronaphthalene, 2-fluorofluorene, 5-fluoroacenaphthylene, 2-fluorophenanthrene, 3-fluorophenanthrene, 3-fluorofluoranthene, 1-fluoropyrene, 1-fluorochrysene, 2-fluorochrysene, 3-fluorochrysene and 9-fluorobenzo[k]fluoranthene. To allow comparison with the corresponding parent PAHs, the 1H and 13C chemical shifts of acenaphthylene, phenanthrene, fluoranthene, pyrene and benzo[k]fluoranthene were determined. Chemical shift increments and the effects on the coupling constants from the fluorine substitution are discussed.

Carbon Isotopes↗
PubMed1996

Oligo-2'-fluoro-2'-deoxynucleotide N3'-->P5' phosphoramidates: synthesis and properties.

Uniformly modified oligodeoxyribonucleotide N3'-->P5' phosphoramidates containing 2'-fluoro-2'-deoxy-pyrimidine nucleosides were synthesized using an efficient interphase amidite transfer reaction. The 3'-amino group of solid phase-supported 2'-fluoro-2'-deoxynucleoside was used as an acceptor and 5'-diisopropylamino phosphoramidite as a donor of a phosphoramidite group in the tetrazole-catalyzed exchange reaction. Subsequent oxidation with aqueous iodine resulted in formation of an internucleoside phosphoramidate diester. The prepared oligo-2'-fluoro-nucleotide N3'-->P5' phosphoramidates form extremely stable duplexes with complementary nucleic acids: relative to isosequential phosphodiester oligomers, the melting temperature Tm of their duplexes with DNA or RNA was increased approximately 4 or 5 degrees C per modification respectively. Moreover, these compounds are highly resistant to enzymatic hydrolysis by snake venom phosphodiesterase and they are 4-5 times more stable in acidic media (pH 2.2-5.3) than the parent oligo-2'-deoxynucleotide N3'-->P5' phosphoramidates. The described properties of the oligo-2'-fluoronucleotide N3'-->P5' phosphoramidates suggest that they may have good potential for diagnostic and antisense therapeutic applications.

Base Sequence↗
PubMed1998

Brain elimination half-life of fluvoxamine measured by 19F magnetic resonance spectroscopy.

OBJECTIVE: This study used fluorine-19 magnetic resonance spectroscopy (19F MRS) to characterize the elimination of fluvoxamine from the human brain after abrupt drug discontinuation. The elimination half-lives of fluvoxamine in brain and plasma were determined to assess their interdependence and the relationship of brain half-life to the clinical practice of drug holidays and reports of acute withdrawal symptoms. METHODS: Six subjects completing clinical treatment with fluvoxamine were enrolled in the study. Spectroscopic quantification of whole brain fluvoxamine concentrations and chromatographic determination of plasma fluvoxamine levels were performed serially for up to 10 days after drug withdrawal. Psychiatric evaluation to assess withdrawal symptoms was also done at each scanning session. RESULTS: Elimination of fluvoxamine in the brain and plasma was optimally described by first-order kinetics; the mean elimination half-lives were 58 hours and 26 hours, respectively. The mean ratio of fluvoxamine brain elimination half-life to plasma half-life was 2.4. Three of the six subjects experienced mild to moderate withdrawal symptoms between the third and fifth days of the study, which corresponded to between one and two brain half-lives of fluvoxamine. CONCLUSIONS: The brain elimination half-life for fluorinated psychotropic compounds can be measured noninvasively by 19F MRS. The elimination half-life of fluvoxamine was found to be substantially longer for the brain than for plasma. The time course of withdrawal symptom onset and the rationale for drug holidays with fluvoxamine appear to be well explained by the brain elimination half-life.

Brain↗
PubMed2004

Reverse fluorous solid-phase extraction: a new technique for rapid separation of fluorous compounds.

Fluorous-tagged compounds can rapidly be separated from organic (non-tagged) compounds by the new separation technique of reverse fluorous solid-phase extraction (r-fspe). In a reversal of the roles of solid and liquid phases in standard fluorous spe, a mixture is charged to a polar solid phase (standard silica gel) and then eluted with a fluorous solvent or solvent mixture. The organic components of the mixture are retained, while the fluorous components pass. [structure: see text]

Chromatography, Gel↗
PubMed2004

Extractionless GC/MS analysis of gamma-hydroxybutyrate and gamma-butyrolactone with trifluoroacetic anhydride and heptafluoro-1-butanol from aqueous samples.

gamma-Hydroxybutyrate (GHB) is a DEA Schedule I drug of abuse commonly spiked into beverages to incapacitate victims of sexual assault. GHB is a challenging drug for analysis by GC/MS because of its small size, charged nature, low volatility, and intramolecular esterification leading to gamma-butyrolactone (GBL). In this work an extractionless technique has been developed that allows for the use of an aqueous sample for direct derivatization. The technique uses a solution of trifluoroacetic anhydride (TFAA) and 2,2,3,3,4,4,4-heptafluoro-1-butanol (HFB) to derivatize the active hydrogens of GHB. The conversion of GBL into GHB can be forced under alkaline conditions by diluting the sample in 10 mM borate buffer, pH 12. GBL found in beverages intended for human consumption is treated as a Schedule I control substance analogue. Spikes of the two compounds into several beverage matrices gave quantitative recovery of GHB by GC/MS. The derivatization produces higher molecular mass products whose fragmentation pattern provides multiple peaks for confirmation and quantification. The concentration of GBL can also be indirectly determined by the method developed. Therefore, this extractionless technique is rapid, sensitive, and selective for the confirmation of the presence of GHB and GBL in commercial beverages.

4-Butyrolactone↗
PubMed2000

Effects of long-term administration of vitamin D3 analogs to mice.

This study explores the effects of chronic administration of vitamin D(3) compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D(3) analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunological disorders and bone diseases. Four unique vitamin D(3) analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) were administered i.p. for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4- to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH)(2)D(3) had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D(3) analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D(3) administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.

Animals↗
PubMed2003

Fluorophobic effect promotes partitioning of organics into macroporous organic polymers: a method for achieving high local concentrations.

The efficiency for partitioning small organic compounds from fluorinated solvents of varying quality into highly cross-linked, macroporous, and insoluble organic polymers is described. The solvating qualities of the poly(acrylates) together with the solvating quality of the solvent are key to describing the partitioning thermodynamics. Partitioning measurements for 9-anthracene methanol 1 are reported as a function of fluorous content in perfluoromethylcyclohexane (PFMC):hexanes mixtures, comonomer structure and loading, and temperature. The best comonomer for the sorption of 1 is methacrylamide. Concentration enhancements of up to approximately 200-fold are obtainable, and are proposed to account for previously observed rate accelerations in catalyst-containing porous polymers. Partition efficiency (PE) measurements, described as the ratio of polymer to original solution concentrations, are presented for a variety of organic compounds. The PE is sensitive to analyte structure and ranges from 1 to 170 (180 being the maximum under the conditions employed), with linear alkanes at the low end of the spectrum and polar functional groups at the opposite.

Journal Article↗
PubMed2001

Unique selectivity of perfluorinated stationary phases with 2,2,2-trifluoroethanol as organic mobile phase modifier.

The selectivity of Luna C18 Xterra C18 and Fluophase (perfluorinated C6) stationary phases has been investigated with aqueous acetonitrile, methanol and 2,2,2-trifluoroethanol mobile phases using linear solvation equations. The gradient retention times of a set of 60 compounds with known molecular descriptors have been determined. Linear solvation equations have been set up to describe the relationship between the gradient retention times and the molecular properties. The selectivity of the stationary phase/mobile phase systems was characterised by the regression coefficients of the molecular descriptors. The perfluorinated stationary phase showed very different selectivity using 2,2,2-trifluoroethanol (TFE) as co-solvent. Compounds with H-bond donor functionality were retained much less than in the other investigated high-performance liquid chromatography (HPLC) systems. This unique selectivity can be explained by the stronger adsorption of trifluoroethanol on the perfluorinated stationary phase surface, than on the hydrocarbon surface. It suggests the importance of the adsorbed organic modifiers in the separation mechanism during reversed-phase HPLC.

Chromatography, High Pressure Liquid↗
PubMed1980

3-Trifluoromethyl-3-phenyldiazirine. A new carbene generating group for photolabeling reagents.

The synthesis of 3-trifluoromethyl-3-phenyldiazirine (TPD) is reported in an overall yield of 60% based on 2,2,2-trifluoroacetophenone as starting material. TPD is rapidly photolyzed on irradiation near 350 nm to yield 35% of the diazoisomer and 65% of the corresponding carbene. No internal rearrangement of the latter compound by fluorine migration was detected. Photolysis in methanol yielded the product of a formal OH insertion in greater than 95% yield. Photolysis in cyclohexane gave at least a 50% yield of the CH insertion product at a diazirine concentration of 15 mM. The products were identified by gas chromatographic mass spectra and by 19F NMR spectra. In the dark the diazirine is stable in 1 M acid or base and at temperatures as high as 75 degrees C for at least 30 min. The diazoisomer is much less photolabile and is stable in 0.1 M acetic acid for at least 12 h. The synthesis of a derivative of TPD containing the 2-hydroxyethyl[O-tosylate] group on the para position of the phenyl ring is described. This compound permits the easy attachment of the TPD function to other molecules. It is suggested that the ease of synthesis, dark stability, rapid photolysis, and reactivity of the carbene may make this group useful in the preparation of various photochemical probes.

Affinity Labels↗
PubMed1999

Synthesis and biochemical evaluation of 3-fluoromethyl-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

A series of 3-fluoromethyl-1,2,3,4-tetrahydroisoquinolines (3-fluoromethyl-THIQs) was proposed, and their phenylethanolamine N-methyltransferase (PNMT) and alpha(2)-adrenoceptor affinities were predicted through the use of comparative molecular field analysis (CoMFA) models. These compounds were synthesized and evaluated for affinity at PNMT and the alpha(2)-adrenoceptor. It was discovered that these compounds are some of the most selective inhibitors of PNMT versus the alpha(2)-adrenoceptor known. To determine the ability of these compounds to penetrate the blood-brain barrier (BBB), a series of THIQs possessing a variety of calculated partition coefficients (Clog P) were assayed using an in vitro BBB model. This study found a good correlation between lipophilicity (Clog P) and BBB permeability, which indicated that THIQs possessing Clog P values of at least 0.13-0.57 should have some penetration into the brain. Two compounds [3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (18) and 3-fluoromethyl-7-cyano-THIQ (20)] possess calculated partition coefficients greater than 0.57 and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200 and thus represent promising leads in the development of highly selective inhibitors of PNMT with the ability to penetrate the BBB.

Adrenal Glands↗
PubMed1999

Alpha-trifluoromethylated acyloins induce apoptosis in human oral tumor cell lines.

Cytotoxic activity of newly synthesized trifluoromethyl ketones and related compounds was studied using two human oral tumor cell lines (HSG and HSC-2). Among them, alpha-trifluoromethylacyloins (1 and 2) were found to induce apoptotic cell death, as judged by the terminal deoxynucleotidyl transferase (TdT) dUTP nick end-labeling (TUNEL) method which detects DNA nick or fragments. Furthermore, the cytoplasm of 1 or 2 treated HSG cells was stained by M30 monoclonal antibody, which detects the product resulting from the cleavage of cytokeratin 18 by activated caspase.

Antineoplastic Agents↗
PubMed2005

[Study on solid phase extraction and spectrophotometric determination of uranium in water with 2-(2-quinolylazo)-5-dimthylaminophenol].

A new chromogenic reagent 2-(2-quinolylazo)-5-Dimthylaminophenol (QADMAP) was synthesized, and its structure was verified by elemental analysis, infrared spectrum, 1H nuclear magnetic resonance spectrum, mass spectrumand UV-spectrum. The color reaction of QADMAP with uranium was studied. In the presence of pH 7.8 buffer solution, when fluorin ion and TritonX-100 medium exist, QADMAP can react with uranium and fluorin to form a stable 1 : 1 : 1 stable complex [F- :QADMAP : U(VI)]. The molar absorptivity is 1.05 x 10(5) L x mol(-1) x cm(-1) at 590 nm. Beer's law is obeyed in range of 0-20 microg/10 mL. The uranium in samples can be enriched and separated by solid phase extraction with TBP resin cartridge. This method is applied to the determination of uranium in water sample. The relative standard deviations are 2.2%-3.6%, and the recoveries are 94%-105%.

Aza Compounds↗