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PubMed1989

Effects of fluorine substitution on the DNA binding and tumorigenicity of benzo[b]fluoranthene in mouse epidermis.

The effects of fluorine substitution on benzo[b]fluoranthene (B[b]F) DNA adduct formation and tumorigenicity in mouse epidermis were investigated. Fluoro derivatives studied included 1-, 6-, 7-, 8-, 9- and 11-fluoroB[b]F as well as 1,9- and 6,9-difluoroB[b]F. Each compound was applied topically to mice and hydrocarbon/DNA adduct formation was assessed using the 32P-post-labelling technique. All of the fluorinated compounds bound to DNA to a lesser extent than B[b]F. Among the fluorinated compounds, the greatest binding was observed for 8-fluoroB[b]F. Lowest levels of hydrocarbon/DNA adduct formation from the fluoro derivatives were observed for 1-, 7-, 11- and 6,9-difluoroB[b]F. The tumor-initiating activities on mouse skin of 7-, 9- and 11-fluoroB[b]F were determined. All three compounds were significantly less tumorigenic than B[b]F. The results of this study are discussed with respect to possible mechanisms of metabolic activation of B[b]F.

Animals↗
PubMed2005

Synthesis of environmentally relevant fluorinated surfactants--a review.

In the past years there has been a growing interest in fluorinated persistent organic pollutants such as perfluorooctanesulfonic acid, perfluorooctanesulfonamides, perfluorinated carboxylic acids and fluorotelomer alcohols. Although these compounds have probably been present in the environment for many decades, we are only now beginning to realize that these environmental contaminants may have serious environmental and health effects. This article gives a state-of-the-art review of synthetic approaches that have been employed for the synthesis of these environmentally relevant fluorinated compounds. Perfluorooctanesulfonic acid derivatives, in particular, pose a problem because only a few perfluorooctanesulfonic acid derivatives are available from commercial sources--a fact that limits the ability of researchers worldwide to further study these compounds. Because of the limited literature available, this article also describes synthetic approaches for shorter chain homologues or perfluoroether analogues that can potentially be applied for the synthesis of perfluorooctanesulfonic acid derivatives. The preparation of typical starting materials for the synthesis of perfluorooctanesulfonic acid derivatives such as the perfluoroalkanesulfonyl fluorides and chlorides will be discussed. Subsequently, their conversion into relevant perfluoroalkane sulfonate salts (R(F)SO3M), sulfonamides (R(F)SO2NH2), N-alkyl sulfonamides (R(F)SO2NHR, R = alkyl), N,N-dialkyl sulfonamides (R(F)SO2NR2, R = alkyl), sulfonamidoethanol (R(F)SO2NRCH2CH2OH, R = -H, -CH3 or -C2H5) and sulfonamidoacetates (R(F)SO2NRCH2CO2H, R = -H, -CH3 or -C2H5) will be described. Many perfluorinated carboxylic acids and fluorotelomer alcohols are available from commercial sources. The review of the synthesis of these two classes of fluorinated compounds includes a review of their industrial synthesis and the synthesis of relevant degradation products.

Alkanesulfonic Acids↗
PubMed2001

Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol analogs: metabolism by CYP1A2.

A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined with recombinant-expressed CYP1A2. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units, in log D by 3 log units, and in size of the added substituents. N-Dealkylation and aromatic hydroxylation (formation of the 4'- and 5'-regioisomers) were catalyzed by CYP1A2. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with physicochemical properties pK(a) and log D showed that increased lipophilicity (higher log D values) was associated with increased affinity (lower K(m)) and increased catalytic efficiency for CYP1A2. Comparison of log K(m) and log k(cat)/K(m) with pK(a) showed that the less basic analogs had higher affinities and increased catalytic efficiencies. The changes associated with pK(a) reflect increased lipid partitioning of substrate (increased log D) caused by an increase in the proportion of nonionized substrate. Increased steric bulk in the N-substituent alone did not decrease substrate affinity for CYP1A2 but did increase the amount of aromatic hydroxylation versus N-dealkylation. Removal of the hydroxyl group from the propanolamine side chain of propranolol resulted in a similar change in regioselectivity of metabolism.

Adrenergic beta-Antagonists↗
PubMed2005

Effects of fluorine substitution on the edge-to-face interaction of the benzene dimer.

To gain some insight into the effects of fluorination on the aromatic-aromatic interactions found in protein-ligand complexes, like those observed in the set of N-(4-sulfamylbenzoyl)benzylamine (SBB) inhibitors bound to Human Carbonic Anhydrase II (HCAII), we have produced potential energy curves for the edge-to-face interactions of a set of fluorinated benzene dimer compounds. All calculations were carried out at the MP2/aug-cc-pVDZ level of theory using the counterpoise method of Boys and Bernardi (Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553) to account for the basis set superposition error. Fluorine substitutions are made onto the face molecule of the edge-to-face benzene dimer. As one might expect, the substitution of additional fluorines into this system generally resulted in a decrease of the binding energy. It was also found that the positioning of the fluorine substituents on isosubstituted compounds has a large effect on the total binding energy of these types of systems. More specifically, complexes with fluorines that are substituted closer to the hydrogen atoms of the edge benzene will tend to be stabilized by an electrostatic interaction between the partially negative fluorine atoms and the partially positive hydrogen atoms. However, our findings do not explain the recent crystallographic findings for the SBB-HCAII protein-ligand complex, where increased fluorination resulted in closer edge-to-face contacts, which suggests that there are factors, other than edge-to-face aromatic interactions, influencing this system's behavior.

Benzene Derivatives↗
PubMed1992

Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography.

We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t1/2 = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5 alpha-dihydrotestosterone (DHT), 7 alpha-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17 beta-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.

Androgens↗
PubMed1989

Characteristics of fluorinated nitroazoles as hypoxic cell radiosensitizers.

Types of 2-nitroimidazoles and 3-nitro-1,2,4-triazoles bearing one or two fluorine atoms on their side chains were synthesized to evaluate their physicochemical properties, radiosensitizing effects, and toxicity. The reduction potential of the compounds containing one fluorine was similar to that of misonidazole (MISO), whereas that of the difluorinated compounds was slightly higher. Both mono- and difluorinated compounds had an in vitro sensitizing activity comparable to or slightly higher than that of MISO. The fluorinated 3-nitrotriazoles were almost as efficient as the 2-nitroimidazoles with the same substituent. In vivo, some of the compounds were up to twice more efficient than MISO, whereas others were as efficient as MISO. Toxicity in terms of LD50/7 in mice was quite variable depending on the side-chain structure; the amide derivatives were less toxic than MISO, whereas the alcohol and ether derivatives were more toxic. In view of the radiosensitizing effect and toxicity in vivo, at least one compound, KU-2285 (a 2-nitroimidazole with an N1-substituent of: CH2CF2CONHCH2CH2OH) has been found to be as useful a hypoxic cell sensitizer as SR-2508.

Animals↗
PubMed2002

Thermophysical properties of fluorinated acrylate homopolymers: mixing and phase separation.

The thermophysical properties of fluorinated acrylate homopolymers are investigated by differential scanning calorimetry (DSC) and optical microscopy and discussed in terms of relative lengths of the fluorinated chain and the hydrocarbon spacer between the acrylate moiety and the fluorinated chain. These compounds exhibit an intrinsic microphase-separation (Isotropic+Isotropic morphology) occurring between the fluorinated chains and the acrylate polymer backbone. It is shown that the enthalpy of mixing is a function of the length of the lateral fluorocarbon chains. The thermophysical behaviour of these materials may be regarded as demixed systems exhibiting an Upper Critical Solution Temperature. The photopolymerization process of one of the monomer is studied by isothermal photocalorimetry. High acrylate double-bond conversion and fast curing rates were obtained thus demonstrating the promising use of these materials for coating and film processing applications using UV-curing techniques.

Journal Article↗
PubMedDate not supplied

Fluorine-fluorine spin-spin coupling constants in aromatic compounds: correlations with the delocalization index and with the internuclear separation.

This paper describes a new empirical approach for the evaluation of fluorine-fluorine spin-spin coupling constants (J(FF)) in aromatic compounds. The correlations between J(FF) and the delocalization index calculated within the framework of the theory of atoms in molecules (AIM) and with the fluorine-fluorine internuclear separation are investigated. Both the internuclear separation and the delocalization index are found to be highly correlated with J(FF). A regression model in which the experimental J(FF) coupling constant is fitted exponentially to the internuclear separation and linearly to the delocalization index yields a squared correlation coefficient as high as 0.96 for a data set consisting of 33 coupling constants spread over a range of 85 Hz.

Fluorine↗
PubMed2005

Stable dispersions of silver nanoparticles in carbon dioxide with fluorine-free ligands.

Iso-stearic acid, a short, stubby compound with branched, methylated tails has been shown to have high solubility in carbon dioxide. Tail solvation by carbon dioxide makes iso-stearic acid a good choice for use as a ligand to sterically stabilize metallic nanoparticles. Iso-stearic acid coated silver nanoparticles have been stably dispersed in carbon dioxide with hexane cosolvent. Neat carbon dioxide has successfully dispersed iso-stearic acid coated silver nanoparticles that had been deposited on either quartz or polystyrene surfaces. These results are the first reports of sterically stabilized nanoparticles in carbon dioxide without the use of any fluorinated compounds.

Journal Article↗
PubMed2001

Benzophenone derivatives and related compounds as potent histamine H3-receptor antagonists and potential PET/SPECT ligands.

Para-substituted aromatic ethers with benzophenone or related structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety were prepared by Mitsunobu-type ether synthesis or SNAr reaction. Most of the title compounds possess high antagonist potency in histamine H3-receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl phenyl methanone as a new lead, structure-activity relationships were investigated for this new class of compounds. Substitution of the meta'-position of the benzophenone moiety with halogen atoms (e.g., iodine, fluorine) led to compounds with high antagonist potency in vitro as well as in vivo (Ki = 9.3 and 4.3 nM, ED50 = 0.7 and 0.47 mg/kg p.o., 18 and 12, respectively). A receptor profile of several functional in vitro assays for several biogenic amine receptors for the meta'-iodinated derivative demonstrated high selectivity toward the histamine H3 receptor.

Animals↗
PubMed2001

Selectivity of stationary phases in reversed-phase liquid chromatography based on the dispersion interactions.

Selectivity of 15 stationary phases was examined, either commercially available or synthesized in-house. The highest selectivity factors were observed for solute molecules having different polarizability on the 3-(pentabromobenzyloxy)propyl phase (PBB), followed by the 2-(1-pyrenyl)ethyl phase (PYE). Selectivity of fluoroalkane 4,4-di(trifluoromethyl)-5,5,6,6,7,7,7-heptafluoroheptyl (F13C9) phase is lowest among all phases for all compounds except for fluorinated ones. Aliphatic octyl (C8) and octadecyl (C18) phases demonstrated considerable selectivity, especially for alkyl compounds. While PBB showed much greater preference for compounds with high polarizability containing heavy atoms than C18 phase, F13C9 phase showed the exactly opposite tendency. These three stationary phases can offer widely different selectivity that can be utilized when one stationary phase fails to provide separation for certain mixtures. The retention and selectivity of solutes in reversed-phase liquid chromatography is related to the mobile phase and the stationary phase effects. The mobile phase effect, related to the hydrophobic cavity formation around non-polar solutes, is assumed to have a dominant effect on retention upon aliphatic stationary phases such as C8, C18. In a common mobile phase significant stationary phase effect can be attributed to dispersion interaction. Highly dispersive stationary phases such as PBB and PYE retain solutes to a significant extent by (attractive) dispersion interaction with the stationary phase ligands, especially for highly dispersive solutes containing aromatic functionality and/or heavy atoms. The contribution of dispersion interaction is shown to be much less on C18 or C8 phases and was even disadvantageous on F13C9 phase. Structural properties of stationary phases are analyzed and confirmed by means of quantitative structure-chromatographic retention (QSRR) study.

Chromatography, Liquid↗
PubMed2001

Enols of amides. The effect of fluorine substituents in the ester groups of dicarboalkoxyanilidomethanes on the enol/amide and E-enol/Z-enol ratios. A multinuclei NMR study.

Condensation of phenyl isocyanate substituted by 4-MeO, 4-Me, 4-H, 4-Br, and 2,4-(MeO)(2) with esters CH(2)(CO(2)R)CO(2)R', R = CH(2)CF(3), R' = CH(3), CH(2)CF(3), CH(CF(3))(2), or R = CH(3), R' = CH(CF(3))(2) gave 17 "amides" ArNHCOCH(CO(2)R)CO(2)R' containing three, six, or nine fluorines in the ester groups. X-ray crystallography of six of them revealed that compounds with > or =6 fluorine atoms exist in the solid state as the enols of amides ArNHC(OH)=C(CO(2)R)CO(2)R' whereas the ester with R = R' = CH(3) was shown previously to have the amide structure. In the solid enols, the OH is cis and hydrogen bonded to the better electron-donating (i.e., with fewer fluorine atoms) ester group. X-ray diffraction could not be obtained for compounds with only three fluorine atoms, i.e., R = CH(2)CF(3), R' = CH(3) but the (13)C CP-MAS spectra indicate that they have the amide structure in the solid state, whereas esters with six and nine fluorine atoms display spectra assigned to the enols. The solid enols show unsymmetrical hydrogen bonds and the expected features of push-pull alkenes, e.g., long C(alpha)=C(beta) bonds. The structure in solution depends on the number of fluorine atoms and the solvent, but only slightly on the substituents. The symmetrical systems (R = R' = CH(2)CF(3)) show signals for the amide and the enol, but all systems with R not equal R' displayed signals for the amide and for two enols, presumably the E- and Z-isomers. The [Enol I]/[Enol II] ratio is 1.6-2.9 when R = CH(2)CF(3), R' = CH(3), CH(CF(3))(2) and 4.5-5.3 when R = CH(3), R' = CH(CF(3))(2). The most abundant enol display a lower field delta(OH) and a higher field delta(NH) and assigned the E-structure with a stronger O-H.O=C(OR) hydrogen bond than in the Z-isomer. delta(OH) and delta(NH) values are nearly the same for all systems with the same cis CO(2)R group. The [Enols]/[Amide] ratio in various solvents follows the order CCl(4) > CDCl(3) > CD(3)CN > DMSO-d(6). The enols always predominate in CCl(4) and the amide is the exclusive isomer in DMSO-d(6) and the major one in CD(3)CN. In CDCl(3) the major tautomer depends on the number of fluorines. For example, in CDCl(3,) for Ar = Ph, the % enol (K(Enol)) is 35% (0.54) for R = CH(2)CF(3,) R' = CH(3), 87% (6.7) for R = R' = CH(2)CF(3), 79% (3.8) for R = CH(3), R' = CH(CF(3))(2) and 100% (> or =50) for R = CH(2)CF(3), R' = CH(CF(3))(2). (17)O and (15)N NMR spectra measured for nine of the enols are consistent with the suggested assignments. The data indicate the importance of electron withdrawal at C(beta), of intramolecular hydrogen bonding, and of low polarity solvents in stabilizing the enols. The enols of amides should no longer be regarded as esoteric species.

Journal Article↗
PubMed1998

Discovery of bioavailable inhibitors of secretory phospholipase A2.

Substrate-mimetic inhibitors of sPLA2 with submicromolar in vitro potency were discovered by use of a novel dual substrate screening strategy. In vivo evaluation of selected inhibitors in the rat carrageenan paw edema model of inflammation, however, indicated that in vitro potency was not a good predictor of in vivo activity. Studies of the metabolic stability of early examples of these inhibitors suggested that the metabolic lability of these compounds was a major contributing factor to the observed weak in vivo activity. In an attempt to achieve improved in vivo activity, we prepared and tested compounds designed to overcome the observed metabolic instability. The design of the new compounds involved two types of changes in the inhibitor molecules. First, the C-2 ester moiety was replaced with an amide function so that direct cleavage by stomach acid and blood esterases at this site was minimized. Second, omega-oxidation of the decanamide moiety was eliminated by substitution of hydrogen with fluorine in this position. Compounds containing fluorine in the terminal positions of the alkyl chain retained sPLA2 inhibitory activity and also possessed improved in vitro metabolic stability and pharmacokinetic parameters relative to nonfluorinated inhibitors in this series. As exemplified by GW 4776, improvements in metabolic stability alone, however, were not sufficient to ensure oral activity. Thus, GW 4776 did not show oral activity in the carrageenan edema model and had only modest activity after i.v. dosing in the same model. In fact, the results for GW 9624 and GW 8219 suggested that factors in addition to potency of sPLA2 inhibition and metabolism affect the observed in vivo activity. Despite the fact that these two compounds varied only by a single oxygen-to-sulfur substitution, one was active whereas the other was not. One possible explanation for the observed variability is a compound-dependent difference in the rate of equilibration into tissue. This possibility is relevant as both the carrageenan paw edema model and the phorbol ester edema model involve a localized inflammation. No measurements were made to assess differences in the distribution of the different inhibitors between the blood and the localized site of inflammation. In summary, a series of bioavailable inhibitors of sPLA2 was prepared using an iterative approach that combined medicinal chemistry, in vitro and in vivo evaluation of biological activity, and metabolic and pharmacokinetic studies. Although some compounds in the series showed in vivo activity, the anti-inflammatory effect observed in animal models was modest and a decision was made to abandon sPLA2 as a molecular target for the development of anti-inflammatory agents.

Animals↗
PubMed2006

Synthesis of methylene- and difluoromethylenephosphonate analogues of uridine-4-phosphate and 3-deazauridine-4-phosphate.

Cytidine triphosphate synthetase (CTPS) catalyzes the formation of cytidine triphosphate from glutamine, uridine-5'-triphosphate (UTP), and adenosine-5'-triphosphate. Inhibitors of CTPS are of interest because of their potential as therapeutic agents. One approach to potent enzyme inhibitors is to use analogues of high energy intermediates formed during the reaction. The CTPS reaction proceeds via the high energy intermediate UTP-4-phosphate (UTP-4-P). Four novel analogues of uridine-4-phosphate (U-4-P) and 3-deazauridine-4-phosphate (3-deazaU-4-P) were synthesized in which the labile phosphate ester oxygen was replaced with a methylene and difluoromethylene group. The methylene analogue of U-4-P, compound 1, was prepared by a reaction of the sodium salt of tert-butyl diethylphosphonoacetate with protected, 4-O-activated uridine followed by acetate deprotection and decarboxylation. It was found that this compound undergoes relatively facile dephosphonylation presumably via a metaphosphate intermediate. The difluoromethylene derivative, compound 2, was prepared by electrophilic fluorination of protected 1. This compound was stable and did not undergo dephosphonylation. Synthesis of the methylene analogue of 3-deazaU-4-P, compound 3, was achieved by ribosylation of protected 4-(phosphonomethyl)-2-hydroxypyridine. Electrophilic fluorination was also employed in the preparation of protected 4-(phosphonodifluoromethyl)-2-hydroxypyridine which was used as the key building block in the synthesis of difluoro derivative 4. These compounds represent the first examples of a nucleoside in which the base has been chemically modified with a methylene or difluormethylenephosphonate group.

Clodronic Acid↗