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PubMed2004

T-maze performance after developmental exposure to 19F tagged 5-HTP in chicks.

Chicks were used as a model to investigate behavioral effects of administering a new compound intended for use with magnetic resonance. The compound has multiple 19F atom tags covalently bonded to the indole ring of 5-hydroxytryptophan (PF-5HTP), the immediate precursor to the neurotransmitter serotonin. On incubation Day 17, 5 microg of PF-5-HTP, an equivalent amount of 5-HTP, or just 200 microL of the weak phosphate buffered saline (PBS) vehicle was injected into the airsac of each egg. Three days after hatching, chicks were isolated at the top of a simple T-Maze which, when traversed correctly, enabled them to return to their brood mates. A second trial in the T-Maze was conducted about three hours later. The brief period of isolation at the start of a trial causes social distress in chicks who are reinforced by returning to the brood. The task was selected as being sensitive to functioning of the serotonin pathways whose development might be altered by administering the compound during brain development. Repeated-measures analysis of variance yielded a statistically significant main effect for trial within groups, but no significant difference between injection groups. Administering a low dose of the fluorine tagged compound during development did not impair performance on this T-maze task.

5-Hydroxytryptophan↗
PubMed2006

Interest of fluorine-19 nuclear magnetic resonance spectroscopy in the detection, identification and quantification of metabolites of anticancer and antifungal fluoropyrimidine drugs in human biofluids.

BACKGROUND: The metabolism of fluorouracil and fluorocytosine, two 5-fluoropyrimidine drugs in clinical use, was investigated. METHODS: (19)F nuclear magnetic resonance (NMR) spectroscopy was used as an analytical technique for the detection, identification and quantification of fluorinated metabolites of these drugs in intact human biofluids as well as fluorinated degradation compounds of fluorouracil in commercial vials. RESULTS: (19)F NMR provides a highly specific tool for the detection and absolute quantification, in a single run, of all the fluorinated species, including unexpected substances, present in biofluids of patients treated with fluorouracil or fluorocytosine. Besides the parent drug and the already known fluorinated metabolites, nine new metabolites were identified for the first time with (19)F NMR in human biofluids. Six of them can only be observed with this technique: fluoride ion, N-carboxy-alpha-fluoro-beta-alanine, alpha-fluoro-beta-alanine conjugate with deoxycholic acid, 2-fluoro-3-hydroxypropanoic acid, fluoroacetic acid, O(2)-beta-glucuronide of fluorocytosine. CONCLUSION: (19)F NMR studies of biological fluids of patients treated with anticancer fluorouracil or antifungal fluorocytosine have furthered the understanding of their catabolic pathways.

Antifungal Agents↗
PubMed2005

Oxoselenido clusters of the lanthanides: rational introduction of oxo ligands and near-IR emission from Nd(III).

Reactions of Ln(SePh)3 with SeO2 in THF give octanuclear oxoselenido clusters with the general formula (THF)8Ln8O2Se2(SePh)16 (Ln = Ce, Pr, Nd, Sm). In this isomorphous series, the eight Ln(III) ions are connected in the center by a pair of mu3-O2- ligands and mu5-Se2- ligands, with 14 bridging and two terminal selenolate ligands capping the cluster surface. Thermal decomposition at 700 degrees C of the Nd compound in vacuo led to the formation of a phase mixture of NdSe2, Nd2Se3, and Nd2O3. Near-IR emission experiments on the (THF)8Nd8O2Se2(SePh)16 and the fluorinated thiolate compound (DME)2Nd(SC6F5)3 demonstrate that clusters with oxo ligands are not only highly emissive, but also they emit at wavelengths not found in conventional oxides.

Journal Article↗
PubMed1989

Structure--activity relationship of quinolones.

The understanding of some structure-activity relationships of quinolones allowed the development of the new fluorinated quinolones, compounds with a major clinical potential. The basic structure of these drugs consists of a substituted pyridine ring and a carboxylic acid ring. The substitution at the first position is vital for antibacterial activity, while the presence of a fluorine atom and a piperazine ring is responsible for a broader spectrum of activity and higher intrinsic potency. Further modifications at side-chains or on the ring structure provide compounds with different pharmacokinetic or/and antibacterial activity. A better understanding of these relationships and correlations with clinical results is essential for the design of new improved derivatives with therapeutic potential.

Chemical Phenomena↗
PubMed1995

1H NMR T1 relaxation rate study on substrate orientation of fluoromethylanilines in the active sites of microsomal and purified cytochromes P450 1A1 and 2B1.

The present study describes 1H NMR T1 relaxation rate studies on fluoromethylanilines bound to the active sites of microsomal and purified cytochromes P450 1A1 and 2B1. From the data obtained, insights into the average orientation of the substrates with respect to the paramagnetic Fe3+ centre in the cytochromes P450 could be derived. Particular attention was paid to a possible extra relaxation pathway for methyl protons compared to the aromatic protons, due to the rotational motion of the CH3 around the sigma-C-CH3 bond. However, this effect appeared to be minimal and to result in at most a few percent underestimation of the actual distance of the methyl protons to the Fe3+ centre. Furthermore, the data obtained demonstrate that all aromatic protons are at about the same average distance from the paramagnetic centre. The results also demonstrate that the fluromethylanilines are bound to the active sites of cytochromes P450 1A1 and 2B1 in a similar way. A time-averaged orientation of the substrate with the Fe3+ above the aromatic ring, with the pi-orbitals of the aromatic ring and those of the porphyrin rings in a parallel position, providing possibilities for energetically favourable pi-pi interaction defines the orientation which best fits the results of the present study. Possibilities for a flip-flop rotation around an axis in the plane of the aromatic ring can be included in this picture, as such rotations would still result in a similar average distance of all aromatic protons to the Fe3+ paramagnetic centre. The results obtained also indicate that possible differences in metabolite patterns resulting from conversion of the fluoromethylanilines by different cytochromes P450, especially P450 1A1 and 2B1, are unlikely to be caused by a specific orientation of the substrate imposed by the substrate binding site of the enzyme.

Aniline Compounds↗
PubMed1989

Detection of the pesticide compound 1080 (sodium monofluoroacetate) using fluorine-19 nuclear magnetic resonance spectroscopy.

Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopic measurements were used to determine the chemical nature and amounts of organofluorine in dosed meat baits. Earlier work implied that sodium monofluoroacetate (compound 1080) in meat baits was broken down into other organofluorine compounds such as fluorocitrate. No chemical evidence was found for such compounds. Only monofluoroacetate was detected in the prepared 1080 bait samples. Once the baits have aged, aqueous extraction fails to recover all the added 1080. Analysis using 19F NMR confirmed that the 1080 present in the aqueous extracts of the bait is recovered by Kramer's liquid chromatography method. It was shown here that the aqueous extracts do not recover all the 1080 in the meat bait.

Animals↗
PubMed2004

Modern synthetic methods for fluorine-substituted target molecules.

Fluorine has come to be recognized as a key element in materials science: in heat-transfer agents, liquid crystals, dyes, surfactants, plastics, elastomers, membranes, and other materials. Furthermore, many fluorine-containing biologically active agents are finding applications as pharmaceuticals and agrochemicals. Progress in synthetic fluorine chemistry has been critical to the development of these fields and has led to the invention of many novel fluorinated molecules as future drugs and materials. As a result of the electronic effects of fluorine substituents, fluorinated substrates and reagents often exhibit unusual and unique chemical properties, which often make them incompatible with established synthetic methods. Thus, the problem of how to control the unusual properties of compounds with fluorine substituents deserves much attention, so as to promote the design of facile, efficient, and environmentally benign methods for the synthesis of valuable organofluorine targets.

Chemistry, Agricultural↗
PubMed1999

Imidazole substituted biphenyls: a new class of highly potent and in vivo active inhibitors of P450 17 as potential therapeutics for treatment of prostate cancer.

3- And 4-imidazol-1-yl-methyl substituted biphenyl compounds (named as meta- and para-substituted compounds) were synthesized bearing additional substituents in 3'-/4'-position as inhibitors of P450 17 (17alpha-hydroxylase-C17,20-lyase). P450 17 is the key enzyme of androgen biosynthesis. Its inhibition is a novel therapeutic strategy for treatment of prostate cancer (PC). Twenty-nine compounds were synthesized by Ar-Mg-Br, Negishi or Suzuki aryl-aryl cross coupling and tested toward human and rat enzyme. Most of the compounds showed moderate to excellent activity against one of the enzymes (0.087 microM < or = IC50 < or = 7.7 microM (ketoconazole: 0.74 microM) for the human enzyme, 0.63 microM < or = IC50 < or = 32 microM (ketoconazole: 67 microM) for the rat enzyme). Interestingly, strong species differences were observed. In addition compounds were tested for inhibition toward P450 arom. The 3-imidazol-1-yl-methyl substituted compounds showed good inhibitory activity of P450 arom, while for the 4-substituted compounds negligible inhibition was found. For the most active group of P450 17 inhibitors, (i.e. the 4-imidazol-1-yl-methyl substituted compounds) a QSAR study was performed for inhibition of the human enzyme leading to the result that a hydrophilic substituent in 3'-/4'-position is very important. The most promising compounds (with respect to activity toward both enzymes) were tested in vivo using SD-rats for reduction of plasma testosterone concentrations 2 and 6 h after single i.p. application. The fluorine substituted compound 8c decreased the testosterone plasma concentration to castration level (after 2 h; 5 mg/kg) showing a biological half live of about 6 h.

Animals↗
PubMed1994

Use of 19F nuclear magnetic resonance spectroscopy for probing substitution of Al for Ga in cloverite.

The synthesis of gallophosphate cloverite in the presence of aluminium leads to a partial substitution of Ga by Al. 27Al and 19F magic-angle spinning nuclear magnetic resonance (MAS NMR) studies on this material confirm this substitution. 27Al MAS NMR shows a broad line at 30 ppm which can be attributed to tetrahedrally coordinated Al in the solid. The 19F MAS NMR results are more complex. The spectrum presents five lines between -68 ppm and -95 ppm which can be assigned to fluorine in D4Rs with variable composition in Ga and Al. Two other lines, at -145.6 ppm and -178.2 ppm, may correspond to impurities and to a fluorine atom in a pseudo-sodalite cage environment, respectively.

Aluminum Compounds↗
PubMed1987

2'-Fluorinated arabinonucleosides of 5-(2-haloalkyl)uracil: synthesis and antiviral activity.

The synthesis of 5-(2-fluoroethyl)-2'-deoxyuridine (FEDU, 4b), its 2'-fluoro analogue 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-(2-fluoroethyl)-1H,3H- pyrimidine-2,4-dione (FEFAU, 4k), and the 2'-fluoro analogue of the potent antiherpes virus compound 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), 5-(2-chloroethyl)-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-1H,3H-pyr imidine - 2,4-dione (CEFAU, 4i), is described. The antiviral activities of these compounds were determined in cell culture against herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV). All compounds were shown to possess significant and selective antiviral activity. FEDU proved less potent than CEDU against VZV replication; however, it was more active against HSV-2. CEFAU showed marked activity against HSV-1, HSV-2, and VZV. The compound containing fluorine at both positions, FEFAU, exhibited the strongest antiviral potency against HSV-1, HSV-2, and VZV. It inhibited HSV-1 at a concentration of 0.03-0.2 microgram/mL, HSV-2 at 0.1-0.3 microgram/mL, and VZV at 0.03 microgram/mL. Neither FEDU nor CEFAU or FEFAU exerted a significant inhibitory effect on cell proliferation at a concentration of 100 micrograms/mL. Thus, the cytotoxicity of these compounds is as low as that of CEDU and compares favorably to that of previously described 2'-fluoroarabinosyl nucleoside analogues.

Antiviral Agents↗
PubMed1998

Synthesis, structure and in vitro anti-human immunodeficiency virus activity of novel 3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles.

A series of novel 1-aryl-3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles, TBZ analogues, were synthesized and investigated as anti-human immunodeficiency virus (HIV) agents in order to study the effects of structural modifications on antiviral activity and cytotoxicity. They were proved to inhibit significantly HIV-1 replication in vitro without showing inhibitory activity on HIV-2 or simian immunodeficiency virus. Their potency was influenced by the presence of suitable substituents in the phenyl ring at C-1 as well as by their stereochemical characteristics. In fact, the most active compound of the series was the trans-1-(2,6-difluorophenyl)-3-methyl-1H,3H-thiazolo[3,4- a]benzimidazole, in which the butterfly-like conformation is stabilized by two intramolecular hydrogen bonds between the fluorine atoms and H-1 and H-3. This was made possible by the trans arrangement of C-1 and C-3 substituents, as shown by X-ray and NMR analysis.

Anti-HIV Agents↗
PubMed1964

STIMULANT ACTIONS OF VOLATILE ANAESTHETICS ON SMOOTH MUSCLE.

A number of volatile anaesthetics, and some compounds synthesized in the search for new anaesthetics, have been tested on guinea-pig intestinal smooth muscle in vitro. All the compounds produced a contractile response. This effect did not correlate well with convulsant activity in vivo among the compounds tested. Two kinds of stimulant effect were distinguishable: (1) Rapid, transient contractions, abolished by cocaine or lachesine; most of the anaesthetics in clinical use had this action. (2) Slow, sustained contractions, unaffected by cocaine or lachesine; this effect predominated among the fluorinated ring compounds. Hexamethonium and mepyramine did not affect the contractile response to any of the compounds. The first type of effect presumably represents excitation of postganglionic nerve cells, while the second type is a direct action on the muscle cell. The action of perfluorobenzene, which is of the latter kind, was studied further. Adrenaline and lack of calcium diminished the contraction in parallel with the contraction to histamine, which suggests that the cell membrane was the site of action; in contrast to the stimulant action of histamine or acetylcholine, the effect was highly temperature-sensitive, being almost abolished by cooling to 32 degrees C, and enhanced at 40 degrees C. The depressant action of anaesthetics on smooth muscle is affected very little by temperature changes. These findings are discussed in relation to other observations which suggest a stimulant action of volatile anaesthetics on excitable tissues. Protein denaturation is tentatively suggested as a mechanism of action.

Acetylcholine↗
PubMed2003

Application of isomorphous replacement in the structure determination of a cubic liquid crystal phase and location of counterions.

A second generation monodendron with dodecyl end-groups based on the AB(3) monomer 3,4,5-trihydroxy benzoate has previously been shown to form a thermotropic cubic phase with Pmthremacr;n symmetry (Balagurusamy et al., J. Am. Chem. Soc. 1997, 119, 1539). A structure consisting of spherical "micelles" was proposed originally, but an alternative choice of structure factor phases, giving a structure of interlocked squashed columns, could not be ruled out by diffraction data on the original material alone. We have therefore synthesized two selectively fluorinated equivalent compounds, the carboxylic acid and its Rb salt, to be able to apply a variant of the isomorphous replacement crystallographic technique. On the basis of the electron density maps of the new labeled compounds, reconstructed using small-angle X-ray diffraction intensities, the interlocking columns model is unequivocally rejected and the spheres model is upheld. Furthermore, the location of the metal cation in the center of the "micelles" is directly confirmed. Micellar diameter was shown to decrease on fluorination of the dodecyl chain ends, and increase significantly on introduction of Rb. This is interpreted in terms of changes in the number of wedge-shaped dendrons fitting into a spherical micelle due to their changing taper angle. It was found that the Rb-rich regions at the centers of six out of eight "micelles" in the unit cell are elongated in the direction of their closest packing. This adds support to the suggestion of a partial "column-like" character of stacked rows of such micelles, consistent with the position of the Pmthremacr;n phase next to the columnar phase in the phase sequence of most taper-shape compounds. The results illustrate the potential of isomorphous replacement, used a great deal in protein crystallography, in structure investigation of liquid crystals and supramolecular soft matter.

Journal Article↗
PubMed2003

Unique bioconcentration characteristics of new aryl fluoroalkyl ethers in common carp (Cyprinus carpio).

The bioconcentration factors (BCFs) of seven new aryl fluoroalkyl ethers--four bis-4-tetrafluoroethoxyphenyl-type (bis-type) compounds and three mono-4-tetrafluoroethoxyphenyl-type (mono-type) compounds--were obtained by bioconcentration tests using common carp. The BCFs of 4 of the 7 ethers were higher than 5000, indicating their high bioconcentration potential. The bioconcentration characteristics of the bis-type compounds were different from those of the mono-type compounds and non-fluoro diphenylmethanes with a similar skeleton structure to the bis-type compounds, in taking longer to reach a plateau and having a slower elimination rate and in their distribution patterns in the fish body. The BCF of 1 bis-type compound was much higher than the value predicted by an accepted correlation equation between BCF and P(ow). In addition, the logP(ow) of the bis-type compounds calculated by commercially available computer software was remarkably different from that measured.

Animals↗
PubMedDate not supplied

Fluorine NMR studies of the metabolism of flumecinol (3-trifluoromethyl-alpha-ethylbenzhydrol).

High-resolution and surface coil fluorine-19 NMR spectroscpies have been used to study the metabolism of the liver inducer 3-trifluoromethyl-alpha-ethylbenzhydrol (flumecinol) in rats. Although the fluorine chemical shift range exhibited by metabolites is small, it is possible to identify a number of metabolites or classes of metabolites by direct examination of urine samples. 3-Trifluoromethyl-4'-hydroxy-alpha-ethylbenzhydrol was confirmed as the primary metabolite at low doses (42 mg/kg). At higher doses other metabolites characterized by ring and side chain hydroxylation or further oxidation of the parent compound become apparent. NMR evidence for two previously unrecognized metabolites is described but these structures have not been identified. Studies of liver induction are reported that show that a single large dose of flumecinol exerts a substantial inducing effect on the number and types of metabolites formed after several hours postingestion. Examination of liver metabolism of the drug in vivo showed a single broad resonance, and it was not possible to obtained resolved signals for individual metabolites under the conditions of these experiments. However, nuclear Overhauser experiments showed that the materials detected in the in vivo experiments do not interact significantly with the macromolecular components of the liver.

Animals↗
PubMed1990

Quinazoline antifolate thymidylate synthase inhibitors: 2'-fluoro-N10-propargyl-5,8-dideazafolic acid and derivatives with modifications in the C2 position.

The synthesis of 2'-fluoro-10-propargyl-5,8-dideazafolic acid and its 2-desamino, 2-desamino-2-hydroxymethyl, and 2-desamino-2-methoxy analogues is described. In general the synthetic route involved the coupling of diethyl N-[2-fluoro-4-(prop-2-ynylamino)benzoyl]-L-glutamate with the appropriate 6-(bromomethyl)quinazoline followed by deprotection with mild alkali. These four compounds together with the 2-desamino-2-methyl analogue were tested for their activity against L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of the L1210 cell line and of two mutant L1210 cell lines, the L1210:R7A that overproduces dihydrofolate reductase (DHFR) and the L1210:1565 that has impaired uptake of reduced folates. Compared with their non-fluorinated parent compounds, the 2'-fluoro analogues were all approximately 2-fold more potent as TS inhibitors. Similarly, they also showed improved inhibition of L1210 cell growth (1.5-5-fold), and this activity was prevented by co-incubation with thymidine. All had retained or improved activity against both the L1210:R7A and L1210:1565 cell lines.

Animals↗