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PubMed2004

Perfluorooctane sulfonate (PFOS) and related perfluorinated compounds in human maternal and cord blood samples: assessment of PFOS exposure in a susceptible population during pregnancy.

Fluorinated organic compounds (FOCs), such as perfluorooctane sulfonate (PFOS), perfluoro-octanoate (PFOA), and perfluorooctane sulfonylamide (PFOSA), are widely used in the manufacture of plastic, electronics, textile, and construction material in the apparel, leather, and upholstery industries. FOCs have been detected in human blood samples. Studies have indicated that FOCs may be detrimental to rodent development possibly by affecting thyroid hormone levels. In the present study, we determined the concentrations of FOCs in maternal and cord blood samples. Pregnant women 17-37 years of age were enrolled as subjects. FOCs in 15 pairs of maternal and cord blood samples were analyzed by liquid chromatography-electrospray mass spectrometry coupled with online extraction. The limits of quantification of PFOS, PFOA, and PFOSA in human plasma or serum were 0.5, 0.5, and 1.0 ng/mL, respectively. The method enables the precise determination of FOCs and can be applied to the detection of FOCs in human blood samples for monitoring human exposure. PFOS concentrations in maternal samples ranged from 4.9 to 17.6 ng/mL, whereas those in fetal samples ranged from 1.6 to 5.3 ng/mL. In contrast, PFOSA was not detected in fetal or maternal samples, whereas PFOA was detected only in maternal samples (range, < 0.5 to 2.3 ng/mL, 4 of 15). Our results revealed a high correlation between PFOS concentrations in maternal and cord blood (r2 = 0.876). However, we did not find any significant correlations between PFOS concentration in maternal and cord blood samples and age bracket, birth weight, or levels of thyroid-stimulating hormone or free thyroxine. Our study revealed that human fetuses in Japan may be exposed to relatively high levels of FOCs. Further investigation is required to determine the postnatal effects of fetal exposure to FOCs. Key words: cord blood, fluorinated organic compounds, human, PFOA, PFOS, PFOSA, pregnancy.

Adolescent↗
PubMed2003

Enzymatic assay for perfluoro-tagged metabolites of l-DOPA using crude lysate from E. coli transformed with pKKAADCII.

Isomers of l-DOPA and dopamine with a nine-atom 19F atom tag were exposed to aromatic acid decarboxylase (AADC) in the lysate of Escherichia coli JM109 that had been transformed with the plasmid pKKAADCII. The resulting samples were analyzed with HPLC. The first study investigated the conversion of the tagged l-DOPA into tagged dopamine, using the tagged dopamine as a standard. A second study was undertaken to identify the source of peaks seen in the enzymatic assays. l-DOPA with the tag bonded at position 5 served as the best substrate for AADC. Isomers that fit into the active site of AADC are likely to follow the biosynthetic path for dopamine in vivo and are potentially useful in magnetic resonance studies. The enzymatic assay described here provides an efficient and cost-effective tool for screening new compounds for use in the fluorine imaging of neural pathways.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed2001

Cross-correlated (19)F relaxation measurements for the study of fluorinated ligand-receptor interactions.

Fluorine is often used in drug-design efforts to enhance the pharmacokinetic properties of biologically active compounds. Additionally fluorine nuclei ((19)F) have properties that are well suited to current pharmaceutical NMR screening programs. Together, these considerations have motivated our interest in the utility of fluorine relaxation parameters to study ligand-receptor interactions. Here, we investigate the potential for cross-correlated relaxation effects between the (19)F anisotropic chemical-shift and (19)F-(1)H dipole-dipole relaxation mechanisms to help pinpoint and quantify exchange processes. Methods are proposed and demonstrated in which the magnitude ratio of the transverse cross-correlation rate constant eta(xy) and the fluorine transverse relaxation rate constant, R(2), help estimate the exchange rate constant for ligand-binding equilibria. These exchange rate constants provide estimates of the ligand dissociation rate constants k(off) and can thus provide a means for rank-ordering the binding affinities of ligands identified in pharmaceutical screens.

Algorithms↗
PubMed2006

Fluorinated molecules as drugs and imaging agents in the CNS.

The strategic use of fluorine substitution in drug discovery and drug development is well documented. The small size and high electronegativity of fluorine are among properties of this element that lend special advantages. Applications in drugs targeted to the central nervous system (CNS) have been particularly fruitful in addition to favorable properties seen in many peripherally acting drugs. Fluorine substitution can be used to solve problems unique to the CNS, such as blood brain barrier (BBB) penetration. Likewise, use of the positron emitting isotope, (18)F, provides a unique tool for non-invasive imaging and diagnoses in the CNS. In this review, fluorine in CNS drugs and drug discovery are discussed.

Animals↗
PubMed1999

Characterization of human brain pharmacokinetics using a two-compartment model.

We developed a two-compartment pharmacokinetic model to systematically characterize 19F magnetic resonance spectroscopy (19F MRS) data on the concentration time course of psychotropic compounds measured in human brain. Using this model, brain volume of distribution and clearance were calculated for fluvoxamine as an index compound. Our interest in formalizing a multicompartment model was motivated by recent advances in the field of brain spectroscopy that allow the noninvasive characterization of brain uptake and elimination half-lives of fluorinated psychotropic compounds. Differences between central compartment single-dose and steady-state half-lives and the peripheral elimination half-life at steady state were used to formulate the model. Application of the model is illustrated using previously published data on the elimination half-lives of fluvoxamine from plasma and brain at steady state, along with the literature values for single-dose plasma elimination half-life. Applying the model, brain volume of distribution (1.12 L/kg +/- 0.2 SEM) and clearance (1.01 L/hour +/- 0.12 SEM) were calculated for fluvoxamine. The bioavailability of fluvoxamine to the brain from plasma was 1.85 +/- 0.23 SEM. The underlying multicompartment pharmacokinetics of fluvoxamine were reflected by the difference between brain and plasma elimination half-lives from steady state. This method to derive pharmacokinetic parameters using 19F MRS measurements of drug concentration in brain can be applied to characterize the pharmacokinetics of other fluorinated psychotropic compounds.

Biological Availability↗
PubMed2002

Synthetic applications of electrophilic fluorodesilylation.

Recently, with the appearance of electrophilic sources of fluorine including the commercially available N-F reagents, the concept of electrophilic fluorodesilylation has emerged as a new strategy to prepare a variety of fluorine containing compounds. This paper highlights how this concept has been applied to the preparation of a series of fluorinated molecules including fluoroaromatic compounds, fluoroalkenes, difluoroamides, difluoroalcohols, difluoroethers and alpha-fluorinated carbonyl derivatives.

Journal Article↗
PubMed2001

Compound-specific, quantitative characterization of organic fluorochemicals in biological matrices.

Since the early 1980s, there has been a steady increase in the use of nonvolatile fluorinated organic compounds for a variety of industrial and commercial applications. The industrial use of these relatively stable compounds has initiated debate over the fate of fluorochemicals in the environment and, ultimately, the bioavailability of these compounds. In this manuscript, we present quantitative results from a study of 65 human sera samples purchased from biological supply companies that provide characterization of specific organic fluorochemicals present in the sera of nonindustrially exposed humans. Summed together, the compound-specific characterization data reported here agree closely with levels of nonspeciated organic fluorine that were originally reported to be present in sera in 1970. The compound-specific method for the extraction of extremely low levels of several commercial organic fluorochemicals from sera and liver with quantitative detection by negative ion electrospray tandem mass spectrometry described represents a robust, previously undescribed approach to quantifying specific organic fluorochemicals in biological matrices.

Environmental Monitoring↗
PubMedDate not supplied

Novel fluorinated hypoxia-targeted compounds as Non-invasive probes for measuring tumor-hypoxia by 19F-magnetic resonance spectroscopy (19F-MRS).

BACKGROUND: 19F-labeled 2-nitroimidazoles bound to hypoxic cells in tumors are known to be useful probes for measuring hypoxia, since they can allow their non-invasive detection to be carried out by 19F nuclear magnetic resonance. MATERIALS AND METHODS: Seven different multifluorinated nitroimidazole-based compounds have been synthesized to furnish this aim: N,N-bis(m-trifluoromethylbenzyl)-3-(2-nitro-1-imidazolyl)propylamine hydrochloride (Bis-mTFN-1); N,N-bis(p-trifluoro-methylbenzyl)-3-(2-nitro-1-imidazolyl)propylamine hydrochloride (Bis-pTFN-1); N-3,5-di-trifluoro-methylbenzyl, 3-(2-nitro-1-imidazolyl)propylamine hydrochloride (DiCF3); N-(m-trifluoromethyl-benzyl)-3-(2-nitro-1-imidazolyl)-propylamine hydrochloride (mTFN-1); N-(p-trifluoromethylbenzyl)-3-(2-nitro-1-imidazolyl)propylamine hydrochloride (pTFN-1); N-(p-trifluoromethylbenzylcarbonyl)-3-(2-nitro-1-imidazolyl)propylamine (pTFA-1) and 5,6-dimethyl-4-[3-(2-nitro-1-imidazolyl)propylamino]-2-trifluoromethylpyrimidine hydrochloride (CF3PM). The compounds were studied in V79 cells in vitro, whereas selected compounds were tested for systemic toxicity in BALB/c mice. RESULTS: With the exception of pTFA-1, all compounds were soluble in water or saline. All compounds were stable at room temperature as solids, or at 0-5 degrees C as aqueous solutions. Very good uptake were obtained in aerobic V79 cells with selected compounds. Thus, intracellular vs. extracellular concentration ratios (Ci/Ce) were increasing with input concentration up to 200. All compounds behaved as hypoxia-selective cytotoxins in V79 cells, in vitro, with selectivity ranging between 2.0 (DiCF3) to 15.5 (CF3PM). No lethality or body weight loss was observed with all tested compounds. Some signs of neurotoxicity were seen with bis-pTFN-1, mTFN-1 and pTFN-1 at the higher tested i.p. doses. No adverse effects were observed with CF3PM at any tested dose. CONCLUSION: These results suggest that some of the above compounds could be utilized as 19F-MRS probes for measuring tumor-hypoxia, by accumulation and binding into the hypoxic regions of tumors.

Animals↗
PubMed2001

Antitumor efficacy of 26-fluoroepothilone B against human prostate cancer xenografts.

BACKGROUND: Epothilone compounds (e.g. epothilones A and B) represent a new structural class of microtubule inhibitors with the remarkable ability to inhibit tumor growth of multidrug-resistant cell lines at low nanomolar or even subnanomolar concentrations. Unfortunately, this therapeutic efficacy has only been achieved to date with a narrow therapeutic window. Hence, other structural analogs of compounds such as epothilone B are currently being synthesized in the hope that they will demonstrate equivalent antitumor efficacy with reduced systemic toxicity. PURPOSE: To evaluate the relative efficacy and toxicity of selectively modified epothilone compounds. METHODS: Compounds were initially screened for relative cytotoxicity against the human prostate cancer cell lines PC3, LNCaP, MDA PCa 2a and MDA PCa 2b. Growth inhibitory IC50 values of 0.5 to 4 nM were obtained. From this initial screen, one epothilone compound, 26-fluoroepothilone B, was chosen for further evaluation against the growth of s.c.-implanted MDA PCa 2b- and PC3-derived prostate tumors in athymic nude mice. The compound was administered intravenously at 2, 5 and 10 mg/kg after the tumors had reached 300 mm3. Two control groups were used: paclitaxel (40 mg/kg) and saline. RESULTS: Following treatment with 10 mg 26-fluoroepothilone B/kg, there was a sustained decrease in tumor size for 30 days reaching a maximal reduction of 80% when compared with tumor growth in the saline control group. Sustained suppression (> 20 days) of tumor growth was observed following the second drug injection. Although a maximal body weight loss of 30% occurred after the second injection, all mice completely regained their initial body weight in 20 days. A lower dose (2 mg/kg) produced a 58% maximal reduction in tumor size and a 20% body weight loss. Minimal inhibition of tumor growth, however, was obtained with paclitaxel at a maximally tolerated dose (40 mg/kg). Other epothilones tested were either less effective and/or more toxic than 26-fluoroepothilone B. This new fluorinated epothilone compound supports the growth of paclitaxel-dependent Tax-18 mutant CHO cells and produces microtubule bundles similar to those produced by paclitaxel, indicating that the two drugs share a similar mechanism of action. CONCLUSION: A new fluorinated epothilone compound, 26-fluoroepothilone B, has been described that stabilizes microtubule structures based on its support of growth of a mutant paclitaxel-dependent CHO cell line. Its antitumor activity against human prostate cancer in nude mice is superior to that of paclitaxel at equivalent toxic doses. Further research is required to determine optimal dosing strategies and to fully assess the compound's activity against other malignant diseases.

Animals↗
PubMed1990

Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV.

2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.

Antiviral Agents↗
PubMed2005

[The comparative study of the effect of new fluorine-containing guanidine-derivate compounds and pinacidil on contractile function of the urinary bladder in vitro].

The effects of the new fluorine-containing guanidine-derivate compounds on bladder contractile functionwere examined on isolated bladder strips in vitro. Female rats (250-350 g) were used. The bladder was removed and placed in the room temperaturePSS of the following composition (mM): NaCl (118.4), KCl (4.7),CaCl2 (2.5), MgSO4 (1.2), KH2PO4 (1.2), NaHCO3 (24.9), and D-glucose (11.1) gassed with O2-CO2. 95%-5%. The base of the bladder was then cut into strips 4-to 5-mm wide and 10-mm long. Then strips were pretensioned (0.25-0.5 g) and after 30 min of equilibration were contracted with an additional 60 mM KCl and again were allowed to equilibrate. Compounds were administered directly into the tissue bath. All compounds produced a concentration-dependent relaxation of isolated rat bladder strips.

Adenosine Triphosphate↗
PubMed2001

Qualitative and quantitative analyses of resin-bound organic compounds.

Methods for qualitative and quantitative analyses of resin-bound organic compounds are essential tools for chemistry development in solid-phase combinatorial and parallel syntheses. Here we discuss the use of gel-phase 19F NMR, the fluoride ion-selective electrode method, and spectrophotometry for monitoring solid-phase reactions. Our results indicate that the application of these diverse methods for analyzing the outcome of solid-phase combinatorial synthesis are sensitive and conclusive.

Aldehydes↗
PubMed2003

Syntheses of selectively fluorinated cyclodecenones: the first deployment of the neutral oxy-Cope rearrangement in organofluorine chemistry.

Metallated haloalkenes were used to open epoxides in moderate to good yield. The homoallylic alcohols obtained underwent Swern oxidation to afford three gamma,gamma-difluorinated beta,gamma-enones, which reacted with either vinyllithium,2-lithio-2H-dihydropyran or another metallated haloalkene to afford substituted trans-1,2-divinylcyclohexanols of different degrees of stability. These intermediates underwent neutral thermal oxy-Cope rearrangements when heated in xylene in Ace tubes. The first-formed enols ketonised without loss of HF to afford a range of cyclodecenones in moderate to good yield; X-ray crystallography was used extensively for product characterisation. All substrates rearranged more rapidly than a cis/trans mixture of 1,2-divinylcyclohexanols.

Crystallography, X-Ray↗