Isolation and properties of a thrombin-sensitive protein of human platelets.
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Acetates↗
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Cholinergic activities of halogeno-acetylcholines.
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Acetylcholine↗
The effects of inhibitors of adenosine 5'-triphosphate biosynthesis on the responses of the guinea-pig isolated bladder and some other preparations to nerve stimulation.
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Adenosine Triphosphate↗
The action of selected agents on the accumulation of 18F by Streptococcus mutans.
The action of certain substances known to induce cellular alterations, or encounted in the oral cavity, on the accumulation of 18F by Streptococcus mutans GS-5 has been investigated. A 62-67% inhibition in the number of 18F atoms bound per mg dry weight of cells could be induced by a 15 min pretreatment with 2.7 X 10(-4) M cetyltrimethylammoniumbromide, 1 X 10(-1) M acetic anhydride, or 7 X 10(-2) M HCl. Plate counts indicated that alteration of the cellular composition rather than viability was responsible for this diminution in 18F accumulation. Prior exposure for 15 min of this organism to 1 M HCHO or 0.1 M NaOH did not alter 18F accumulation. Of the common salts encountered in the oral cavity, CaCl2 enhanced 18F binding. Pretreatment of the assay cells for 15-160 min with 0.1-10 mg/ml of trypsin, pronase, protease, alpha-glucosidase, dextranase, or lactoferrin had no significant effect on the accumulation of 18F. However, pre-exposure of cells for 60 min to 1-10 mg/ml of either amylase or lipase induced a 40-67% inhibition in the binding of 18F, while lysozyme enhanced the binding of 18F by the cells. It would appear then that the binding of 18F by S. mutans may be altered by certain substances encountered in the oral cavity.
Acetic Anhydrides↗
Antiproliferative activity of colchicine analogues on MDR-positive and MDR-negative human cancer cell lines.
In this study the in vitro antitumor activity of a series of 20 colchicine analogues was tested and compared with colchicine and thiocolchicine on three different human cancer cell lines, two of which express the multidrug-resistance (MDR) phenotype. At concentrations from 1 nM to 100 microM, all compounds tested inhibited cancer cell proliferation. The IC50 values indicate that the three fluorinated analogues were the most active compounds, with a similar decreasing order of potency (IDN 5005 > IDN 5079 > IDN 5080) on the two MDR-expressing cell lines, whereas thiocolchicine was the most effective compound on the MDR-negative MDA-MB 231 cells. A strong correlation (r = 0.94; P = 0.004) was found between IC50 values obtained using the two MDR-positive cell lines. Conversely, IC50 values obtained in MDA-MB 231 cells did not show a significant correlation with MDR-positive cell lines, thereby suggesting some difference in the antiproliferative mechanism(s) of colchicine analogues. Cell cycle analysis of the most active analogues in breast cancer cells showed a relationship between cell cycle blocking activity and growth inhibition. The most active agents on the MDR-positive MCF7 ADRr cell line, after 24 h of culture, in terms of cell cycle blocking activity were the three fluorinated analogues. Interestingly, after 72 h, when the cell cycle block subsided, a consistent amount of DNA fragmentation was evident. The extent of cell cycle block, measured as the G2/G1 ratio, was significantly correlated with the apoptosis rate expressed as a percentage of DNA fragmentation on both cell lines, thereby suggesting that a large number of blocked cells underwent the apoptotic pathway.
Antineoplastic Agents↗
Attaching the fluorine atom to organic molecules using BrF3 and other reagents directly derived from F2.
Elemental fluorine is a starting point for nucleophilic fluorinations (e.g., BrF3), radical fluorinations (e.g., F2 under irradiation), and electrophilic fluorinations (e.g., AcOF). All three categories are represented in this Account. Bromine trifluoride, although commercially available, can be readily made from the elements and is a very good source for naked nucleophilic fluoride ions. To minimize radical reactions, an anchor has to be installed in the molecules with which it reacts. Such an anchor is constituted of a soft base such as nitrogen and especially sulfur atoms. This reagent was used for constructing compounds with a CF2, CF3, CHF2, or CF2COOH group in specific sites. F2 itself was used for completing perfluorination of various polyfluoroethers, while the electrophilic acetyl hypofluorite is an excellent tool for introducing a single fluorine atom into organic molecules such as carboxylic acids and nitro compounds.
Bromine↗
Aqueous solubilization of highly fluorinated molecules by semifluorinated surfactants.
The physical and chemical properties of organic compounds are deeply affected by the introduction of fluorinated substituents. Perfluorinated and highly fluorinated organic molecules are both hydrophobic and lipophobic. This makes the recognition and the binding of fluorinated molecules extremely difficult to achieve through classical elements of molecular recognition. Here we show that semifluorinated water-soluble block copolymers can generate micellar structures having a fluorous phase-based inner core in aqueous solution. Furthermore, we show that these micelles can be used to encapsulate and bind highly fluorinated molecules through association in the internal fluorous phase (fluorophobic effect). We report that semifluorinated block copolymers can be used for the aqueous solubilization of the widely diffused gaseous anesthetic sevoflurane, thereby suggesting the possibility of the intravenous delivery of this commonly used anesthetic.
Anesthesia, Inhalation↗
3-Fluoropiperidines and N-methyl-3-fluoropiperidinium salts: the persistence of axial fluorine.
It has previously been shown that the fluorine atom in N-protonated 3-fluoropiperidine salts in water strongly prefers the axial orientation in the six-membered ring chairs. In the present work we examine the proposition that the N-methyl salts are equally disposed to present axial fluorine. Initially, we explored this point by comparing the structures of the corresponding NH2+, NHMe+, and NMe2+ salts by means of density functional theory (DFT), ab initio, and MMFF force field calculations with and without aqueous solvation models. The predictions unambiguously pointed to axial fluorine for all salts investigated, including those with simultaneous axial F and (N)Me. The calculations were followed by synthesis of the corresponding series of 4,4-diphenylpiperidinium salts. These were evaluated by one- and two-dimensional NMR spectroscopy in [D6]DMSO to fully corroborate the axial disposition of the fluorine in each of the compounds. X-ray crystal structure determinations were likewise performed for the diphenyl-3-fluoro NH2+ and NMe2+ systems to substantiate axial-F. Comparison of the X-ray structures of the fluorinated and unfluorinated NMe2+ salts reveals that the fluorine resides axial in spite of substantial steric compression. While the charge-dipole phenomenon responsible for the axial-F conformation in the parent protonated fluoropiperidinium compounds carries over to doubly alkylated salts, we show that it extends to molecular orientation in the packing of the unit cells in the solid state as well. Finally, using the computational methods that successfully motivated our synthesis and structural work, we have made predictions for a number of new structures and re-examined some parallel results reported by the Eliel group in the early 1970s. Although C-F...H-N hydrogen bonds are reported to be weak and few in number, the CF...HN charge-dipole orienting effect is a powerful directing force that matches the hydrogen-bond in both its energetic contribution and conformational consequences.
Crystallography, X-Ray↗
Fluorinated 2-nitroimidazole derivative hypoxic cell radiosensitizers: radiosensitizing activities and pharmacokinetics.
PURPOSE: To assess the effects of incorporation of a CF2 group into the side chain of a 2-nitroimidazole derivative, we evaluated the in vitro and in vivo radiosensitizing activities of KU-2285 (a 2-nitroimidazole derivative with an N1-substituent of -CH2CF2CONH(CH2)nOH, n = 2) and its related compounds in comparison with those of comparable nonfluorinated compounds. The pharmacokinetics of these compounds in murine tumors was also tested. METHODS AND MATERIALS: KU-2285, KU-3202 (n = 3) and KU-3207 (n = 4) are fluorinated 2-nitroimidazole derivative compounds with similar structures. Etanidazole (a 2-nitroimidazole derivative with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds, KU-3205 (n = 3) and KU-3206 (n = 4) were also tested. The in vitro radiosensitizing activities of each compound for hypoxic cells was evaluated with a standard colony formation method. The in vivo radiosensitizing activities of these compounds were tested in female C3H/He mice bearing SCCVII tumors using an in vivo/in vitro clonogenic assay. The pharmacokinetic studies were performed in C3H/He mice bearing the SCCVII tumor. Samples were analyzed by reverse-phase high-performance liquid chromatography. RESULTS: The in vitro radiosensitizing activities of fluorinated 2-nitroimidazoles were higher than those of the nonfluorinated compounds. Although the in vivo radiosensitizing activity of KU-2285 was higher than that of etanidazole (p < 0.05), other fluorinated 2-nitroimidazoles showed less radiosensitizing activity than the comparable nonfluorinated compounds. The compound was eliminated from serum more rapidly with the increase in the number of CH2 group in the side chain of the compound in each series. CONCLUSION: Although the in vitro sensitizing activity of the fluorinated compounds was higher than that of the comparable nonfluorinated compounds, the in vivo radiosensitizing activity of all fluorinated compounds but KU-2285 was lower than that of comparable etanidazole group compounds, probably due to their lower molecular concentrations in tumor and rapid elimination.
Animals↗
Solving problems fluorine 19F with NMR spectroscopy.
Fluorine 19F is one of few 'lucky' elements found in living organisms, whose nucleus is characterised by non-zero spin, which makes it possible to detect fluorine and to analyse (and image) its chemical compounds with the help of Nuclear Magnetic Resonance (NMR). Fluorine 19F spectroscopy is not as popular as that of hydrogen 1H or phosphorus 31P, however, this method has recently been developed and applied (in medicine, too) more and more frequently, despite technical problems. This paper is a brief introduction to the techniques of investigating fluorine 19F with NMR spectroscopy, providing insight into the peculiarities and the difficulties associated with this method. It is also a short review of the achievements in NMR fluorine investigations in the fields of biology and medicine.
Animals↗
Synthesis and analysis of mixed chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans and assessment of formation and occurrence of the fluorinated and chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans.
Various mixtures of chlorinated-fluorinated dibenzodioxins (PCFDD), dibenzofurans (PCFDF) and biphenyls (PCFB) were synthesized. For trace analysis, we compared the behavior of PCFDD/PCFDF and chlorinated congeners in extraction, enrichment and clean-up steps. To establish GC/MS analysis, various columns were tested, temperature programs were optimized and for MS-identification specific masses were selected from the mass spectra. To evaluate the possibility of formation of these compounds in thermal processes, samples from the aluminum-producing industry and products of pyrolysis of chlorofluoro- hydrocarbons (FCKW) on a laboratory scale were analyzed. At present, the most important potential sources of fluorinated or mixed chlorinated-fluorinated dioxins, furans and biphenyls - combustion processes and large scale chemical production - do not cause significant environmental contamination at least in the areas considered. However, in a sample of filter dust from the refining process of aluminum using freon 12 we found high amounts (4.5 g/kg !) of chlorinated and chlorinated-fluorinated aromatic compounds including chlorinated-fluorinated dibenzofurans and biphenyls. Since the FCKW ban in Europe, this procedure was modified in 1992, replacing freon 12 by a mixture of chlorine and argon. The PFDD/PFDF concentration in the fluorophenols was between 0.45 and 120 micrograms/kg. The fluorobenzenes analyzed contained between 15 and 70 mg/kg fluorinated biphenyls.
Benzofurans↗
Direct spectroscopic observation of inner and outer hydrocarbon chains of lipid bilayer vesicles.
Distearoylphosphatidylcholines labeled with gem-difluoro groups at selected positions of the fatty acid chains have been prepared. These lipids were incorporated into sonicated vesicles and were examined by fluorine nuclear magnetic resonance spectroscopy. All spectra are characterized by two well-separated fluorine resonances. Paramagnetic ions added to the exterior solution of vesicles of fluorinated lipid broaden the upfield resonances, whereas ions trapped in the vesicles interior broaden the downfield resonances. This demonstrates that the fluorine chemical shift of these compounds is sensitive to differences between the inner and outer monolayers of sonicated vesicles.
Fluorine↗
Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates.
Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.
Buffers↗
Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles.
It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.
Administration, Oral↗
Oxohexestrol derivatives labeled with fluorine-18. Synthesis, receptor binding and in vivo distribution of two non-steroidal estrogens as potential breast tumor imaging agents.
We have prepared two non-steroidal estrogens in the 2-oxohexestrol series labeled with the positron-emitting radionuclide fluorine-18, 1-fluoro-5-oxohexestrol (4) and 1-fluoro-2-oxohexesterol (5). We anticipated that the polar ketone function at the interior of these ligands would reduce their level of non-specific binding, which might increase the selectivity of their uptake in vivo. The two compounds were prepared by total synthesis: compound 4 was prepared in fluorine-18 labeled form by [18F]fluorine ion displacement on a suitably protected methanesulfonate precursor followed by deprotection under acidic hydrogenolytic conditions; the isomer 5 was prepared from a protected alpha-keto trifluoromethanesulfonate precursor with deprotection under basic conditions as the final step. The binding affinity of these hexestrol derivatives for the estrogen receptor was determined by competitive radiometric binding assays at 0 and 25 degrees C, and their lipophilicity (as octanol-water partition coefficients, log P values) and non-specific binding were estimated. The log P values determined by a reversed phase HPLC method were higher, relative to estradiol, than those calculated by the fragment method of Rekker. In tissue distribution studies in immature (50 g) rats, both of these compounds showed selective uptake in estrogen target tissues. At 1 h, activity in the uterus reached the level of 2.5-3.0% of the injected dose per gram tissue, with uterus-to-blood and uterus-to-muscle ratios of 14-20 and 8-14, respectively. The uptake efficiency and selectivity of these fluoro-oxohexestrols in principal estrogen target tissues is less than that of fluorine-18 labeled steroidal estrogens we have prepared previously, but their receptor-mediated uptake in certain secondary target tissues is substantial. The specific and non-specific components of target tissue uptake of these two compounds appear to be directly related to their non-specific binding and their binding selectivity.
Animals↗
Ca(2+)-dependent production of reactive oxygen metabolites by human neutrophils in response to fluorinated propranolol analogues.
Fluorinated analogues of propranolol, namely trifluoroethyl propranolol (F3), pentafluoropropyl propranolol (F5), and heptafluorobutyl propranolol (F7), were found to induce reactive oxygen metabolite (ROM) production in human neutrophils in a dose-dependent manner. Preincubation of neutrophils with the calcium chelator BAPTA-AM or the tyrosine kinase inhibitor genistein inhibited this ROM production. Direct measurements of intracellular calcium revealed that these analogues caused a transient increase in intracellular calcium. In addition, these fluorinated analogues of propranolol caused a transient increase in actin polymerization. The effects of these compounds were found to be dependent upon the degree of fluorination of the parent compound. Propranolol, on the other hand, had no direct effect on ROM, calcium, or actin polymerization when added alone to neutrophils, although it did modify responses of cells to various stimuli. Whereas ROM production induced by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was enhanced in a dose-dependent manner, the response to the particulate stimulus, latex beads, was abolished.
Actins↗
Synthesis and antibacterial activity of 1-(substituted pyrrolyl)-7-(substituted amino)-6-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acids.
Seventeen quinolone compounds characterized by having a fluorine atom at the 6-position, a substituted amino at the 7-position, and a substituted pyrrolyl at the 1-position were synthesized for the first time. The in vitro antibacterial activities of these compounds against Escherichia coli and Staphylococcus aureus were tested. Among these agents obtained, compound 24 showed significantly enhanced activity against S. aureus. The results indicate that there is much room for modifications at the N-1 position.
4-Quinolones↗
Surfactants usable for electrospray ionization mass spectrometry.
Surfactants suppress the electrospray ionization (ESI) of various compounds. Here we demonstrate that fluorinated surfactants such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOSA) could be employed for ESI-MS without a significant decrease in sensitivity. Both PFOA and PFOSA could be applied to the analysis of ionic and nonionic compounds by micellar electrokinetic chromatography (MEKC)/ESI-MS, although the migration window was limited. Furthermore, in HPLC/ESI-MS, PFOA could function as a paired ion for enzymatically digested peptides as well as sulfonamides and significant effects of PFOA on the signal peak shape, retention times, and sensitivity of the analytes were observed compared to those of trifluoroacetic acid or sodium dodecyl sulfate (SDS). In addition, PFOA was applied to protein analysis by ESI-MS, and superior sensitivity was noted, compared to other surfactants such as octylglucoside, dodecylglucoside, and SDS. Although 21% of the original signal was observed in the presence of 1% PFOA, this surfactant could be easily removed by evaporation, which resulted in the recovery of 96% of the original signal. Because these fluorinated surfactants could also be used for solubilization, extraction, and disaggregation of proteins, they should greatly expand the applicability of the ESI-MS to the biological problems of proteins.
Adrenergic beta-Antagonists↗