Atropisomerism, biphenyls, and fluorine: a comparison of rotational barriers and twist angles.
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Aromatase Inhibitors↗
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Cyclopropane fatty acid synthase from Escherichia coli: enzyme purification and inhibition by vinylfluorine and epoxide-containing substrate analogues.
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Enzyme Inhibitors↗
[Acid-base catalysis of chiral Pd complexes: development of novel asymmetric reactions].
Using a unique character of the chiral palladium complexes 1 and 2, several types of novel catalytic asymmetric reactions have been developed. In contrast to the conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine compounds were activated to form chiral palladium enolates, which underwent the enantioselective Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid activating the electrophiles, formed concomitantly during the formation of the enolates, whereby the C-C bond-forming reaction was promoted. In addition, this palladium enolate chemistry was also applicable to the electrophilic asymmetric fluorination reactions, and thus various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, and oxindoles were fluorinated in a highly enantioselective manner (up to 98% ee). It is advantageous that these reactions were carried out in environmentally friendly alcoholic solvents such as ethanol, and exclusion of air and moisture is not necessary.
Acids↗
Elucidation of enzyme mechanisms using fluorinated substrate analogues.
A great variety of biological reactions that are physiologically important are catalyzed by enzymes. Understanding the reaction course of these enzyme-catalyzed transformations are of significant importance since the insights gained from these experiments may facilitate the design of methods to control or mimic their actions. A common strategy to study enzyme catalyses is to use fluorinated substrate analogues as mechanistic probes, since fluorine is an effective hydroxyl group mimic and can also be used to replace a hydrogen atom. Using fluorinated substrate probes have enabled researchers to obtain crucial information regarding the catalytic mechanism of enzymatic reactions. Many of these compounds are good enzyme inhibitors and have been developed into clinically useful chemotherapeutic agents. This review will discuss some examples of the use of fluorine containing compounds as mechanistic probes/enzyme inhibitors, many of which are selected from our own work.
Catalysis↗
Synthesis and radiation dosimetry of 4-borono-2-[18F]fluoro-D,L-phenylalanine: a target compound for PET and boron neutron capture therapy.
The 18F-labeling of 4-borono-D-L-phenylalanine (BPA), a potential target compound for cancer treatment with boron neutron capture therapy, is described. By direct fluorination of BPA with [18F]AcOF or [18F]F2 followed by HPLC separation, 4-borono-2-[18F]fluoro-D,L-phenylalanine was prepared with radiochemical yields of 25-35% and with a radiochemical purity of over 99%. The tissue distribution study showed that the compound has potential as a tracer for pancreas imaging with positron emission tomography. Radiation dosimetry is also described.
Animals↗
(1)H and (19)F PGSE diffusion and HOESY NMR studies on cationic palladium (II) 1,3-diphenylallyl complexes in THF solution.
THF solutions of the cationic chiral 1,3-diphenylallyl bidentate phosphine complexes [Pd(eta(3)-PhCHCHCHPh)(Duphos)](CF(3)SO(3)), Duphos = 1,2-Bis-((2R,5R)-2,5-dimethylphospholano)benzene), 2, and [Pd(eta(3)-PhCHCHCHPh)(P,S)]BF(4), 4, P,S = [8-((o-(diphenylphosphino)benzyl) thiomethyl]-(7,7'-dimethyl)-exo-norborneol, have been studied via pulsed gradient spin-echo (PGSE) diffusion, (1)H, (19)F HOESY and a variety of other multi-dimensional NMR methods. On the basis of the (1)H, (19)F HOESY data, the anions show a preference for a specific structural position with respect to the eta(3)-PhCHCHCHPh allyl ligand, i.e. the anion does not move evenly around the periphery of the cation. THF is shown to promote significant ion pairing, although neither 2 nor 4 shows 100% ion pairing.
Allyl Compounds↗
Reactions of SF6 with organotitanium and organozirconium complexes: the "inert" SF6 as a reactive fluorinating agent.
The normally remarkably inert SF6 has been found to be quite reactive toward low valent organometallic compounds, under conditions in which usually powerful fluorinating agents may be less reactive. Reaction of SF6 with Ti[1,3-C5H3(t-Bu)2](6,6-dmch)(PMe3), for example, leads to {Ti[1,3-C5H3(t-Bu)2]F2}4 (dmch = dimethylcyclohexadienyl), whose structure is based on a cube of fluoride ions with the ligated titanium centers situated above four coplanar face centers.
Journal Article↗
An investigation of the structure and bond rotational potential of some fluorinated ethanes by NMR spectroscopy of solutions in nematic liquid crystalline solvents.
NMR spectra of 1,2-dibromo-1,1-difluoroethane and 1-bromo-2-iodo-tetrafluoroethane dissolved in nematic liquid crystalline solvents have been analysed to yield the magnitudes and signs of the scalar couplings, J(ij), and total anisotropic couplings, T(ij), between all the (1)H, (19)F, and (13)C nuclei, except for those between two (13)C nuclei. The values obtained for T(ij) in principle contain a contribution from J(ij)(aniso), the component along the static applied magnetic field of the anisotropic part of the electron-mediated spin-spin coupling. Neglecting this contribution allows partially averaged dipolar couplings, D(ij), to be extracted from the T(ij), and these were used to determine the structure, orientational order, and the conformational distribution generated by rotation about the C-C bond. The values obtained are compared with the results of calculations by ab initio and density functional methods. The differences found are no greater than those obtained for similar compounds which do not contain fluorine, so that there is no definitive evidence for significant contributions from J(CF)(aniso) or J(FF)(aniso) in the two compounds studied.
Journal Article↗
[Hypnotic drugs. 2. Reaction of guanidine carboxamide with fluorinated beta-diketones].
Since in the compound class of 2-ureidopyrimidines accessible through condensation of guanidinecarboxamide (1) with beta-diketones, representatives occur possessing hypnotic activity, the range of applicability of this synthesis on the one hand and the properties of the end products as related to their substitution pattern on the other have been investigated further. Thus, it was found tht while condensations of 1 with beta-diketones carrying short-chain fluorinated substituents proceed at room temperature, change to chain elongation requires more drastic reaction conditions. The interaction of 1 with 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedione (2) requiring a reaction time of 2 h and a reaction temperature of 80 degrees C results in carbamoylguanidinium 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4-octen-6-one-4-olate (3).
Chemical Phenomena↗
Structure-activity studies of fluoroalkyl-substituted gamma-butyrolactone and gamma-thiobutyrolactone modulators of GABA(A) receptor function.
Dihydro-2(3H)-furanones (gamma-butyrolactones) and dihydro-2(3H)-thiophenones (gamma-thiobutyrolactones) containing fluoroalkyl groups at positions C-3, C-4, and C-5 of the heterocyclic rings were prepared. The anticonvulsant/convulsant activities of the compounds were evaluated in mice. Brain concentrations of the compounds were determined and the effects of the compounds on [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to the picrotoxin site on GABAA receptors were investigated. The effects of the compounds on GABAA receptor function were studied using electrophysiological methods and cultured rat hippocampal neurons. Fluorination at C-3 results in either subtle or pronounced effects on the pharmacological activity of the compounds. When hydrogens are replaced with fluorines at the methylene carbon of an ethyl group, as in 3-(1,1-difluoroethyl)dihydro-3-methyl-2(3H)-furanone (1), the anticonvulsant actions of the compound are not much changed from those found for the corresponding alkyl-substituted analogue. In marked contrast, fluorination at the methyl carbon of the ethyl group, as in dihydro-3-methyl-3-(2,2,2-trifluoroethyl)-2(3H)-furanone (3), produces a compound having convulsant activity. This convulsant activity seems to be due to an increased affinity of the compound for the picrotoxin site on GABAA receptors caused by an interaction that involves the trifluoromethyl group. Results obtained with gamma-butyrolactones containing either a 3-(1-trifluoromethyl)ethyl or a 3-(1-methyl-1-trifluoromethyl)ethyl substituent indicate that the interactions of the trifluoromethyl group with the picrotoxin binding site are subject to both stereochemical and steric constraints. Sulfur for oxygen heteroatom substitution, as in the corresponding gamma-thiobutyrolactones, affects the type (competitive, non-competitive, etc.) of binding interactions that these compounds have with the picrotoxin site in a complex manner. Fluorination of alkyl groups at the C-4 and C-5 positions of gamma-butyrolactones having convulsant activity increases convulsant potency.
4-Butyrolactone↗
Novel pathways in drug metabolism.
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Acetaldehyde↗
Elimination of difluorocarbene from the molecular ions of alpha, alpha,alpha-trifluorocresols with a fluorine atom migration in an ion trap mass spectrometer.
The elimination of difluorocarbene (CF(2)) from the molecular ions of m-alpha,alpha,alpha-trifluorocresol (MW 162, 1) and p-alpha, alpha, alpha-trifluorocresol (MW 162, 2) upon electron impact have been investigated using a quadrupole ion trap mass spectrometer. This reaction involves a fluorine (F) atom migration from the trifluoromethyl group to the benzene ring. In the case of 1, an F atom migrates via a four-membered ring transition state to give rise to the molecular ion of p-fluorophenol (MW 112, 5) and a small amount of o-fluorophenol (MW 112, 3). On the other hand, in the case of 2, an F atom migrates to the ipso position of the benzene ring via a three-membered ring transition state to give rise to 5(+). These conclusions were confirmed by the comparison of the energy-resolved mass spectra (collision-induced dissociation (CID) spectra versus collision energy) of the m/z 112 ions from 1(+) and 2(+) with those of reference compounds, o-, m- and p-fluorophenol (3-5).
Cresols↗
A versatile synthesis of fluorinated uracils in solution and on solid-phase.
[reaction: see text] An efficient and convenient two-step synthesis of new fluorinated uracils is described. The first step involves the condensation of an ester enolate with a fluorinated nitrile to furnish fluorinated beta-enamino esters. In turn, these compounds react with organic isocyanates or isothiocyanates to give C-6 fluorinated uracils or thiouracils, respectively, in excellent yields. This synthesis has been successfully adapted to solid-phase conditions with high diversity, thereby facilitating the creation of small (thio)uracil libraries.
Hydrocarbons, Fluorinated↗
[House fly development after chitin biosynthesis inhibitor application to eggs].
Nine asymmetrically substituted ureas were bioassayed against house-fly (Musca domestica L.) eggs. The compounds included benzoylaryl urea derivatives, shown in Table I, (compounds 1 and 3-8) and benzoylheteroaryl ureas (2 and 9) which previously revealed effective inhibition of metamorphosis and reproduction when applied in food to the larvae and adults. The benzoyl moiety of the compounds comprise 2,6-disubstituted benzene ring with fluorine atoms (6-9), chlorine atoms (1-2) or fluorine and chlorine atoms (3-5), respectively. The majority of the compounds include aniline derivatives (1, 3-8), except the two containing pyridine ring (2) or pyridone-2 system (9). The eggs of house fly Musca domestica L. (some hours after they were laid) were put on a piece of cloth impregnated with acetone solution of tested compounds in concentrations 0.1 and 0.01%. The hatching of larvae and the later phases of development were observed. From the tested compounds one (no 8 in tab. II) decreased and delayed the hatching, two compounds (no 1 and 4 in tab. II) affected the later stages of development: the number of pupae and adults were decreased.
Animals↗
Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units.
It has been shown that fluorinated analogues of naturally occurring biological active compounds including amino acids often exhibit unique physiological activity. Among wide varieties of fluorine-containing amino acids, nonhydrolyzable phosphoamino acids possessing a substituent of the difluoromethylene (CF(2)) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these classes of nonhydrolyzable phosphoamino acids corresponding to pTyr 3, pSer 4, and pThr 5 with their incorporation into peptides using newly developed deprotecting procedures. In this article, stereoselective synthesis of the CF(2)-substituted pThr mimetics and development of a two-step deprotecting methodology for the nonhydrolyzable analogues are reviewed. In the course of the above synthetic study, we found that gamma,gamma-difluoro-alpha,beta-enoates were reduced to gamma-fluoro-beta,gamma-enoates by organocopper reagents and then applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres, which have served as potential dipeptide mimetics having structural as well as electrostatic similarity to the parent peptide bonds. Furthermore, mechanistic investigation of the organocopper-mediated reduction led us to development of a SmI(2)-mediated approach toward the synthesis of the fluoroalkene isosteres.
Biomimetic Materials↗
2'-Fluoro-2',3'-dideoxyarabinosyladenine: a metabolically stable analogue of the antiretroviral agent 2',3'-dideoxyadenosine.
In this report, we have compared the uptake, metabolism, and relevant enzymology of a novel anti-acquired immunodeficiency syndrome drug, 2'-fluoro-2',3'-dideoxyarabinosyladenine (2'-F-dd-ara-A) with the corresponding properties of its parent compound 2',3'-dideoxyadenosine (2',3'-ddAdo) in three human T cell lines, MOLT-4, ATH8, and CEM. In previous communications, we have reported that the primary route of metabolism of 2',3'-ddAdo in human T lymphoblasts is catabolic, i.e., deamination to 2',3'-dideoxyinosine (2',3'-ddlno). At this point, the metabolic pathway diverges, to result in either cleavage and inactivation of 2',3'-ddlno by purine nucleoside phosphorylase or in 5'-phosphorylation by a phosphotransferase, a reaction that generates 2',3'-inosine monophosphate and ultimately the putative active metabolite 2',3'-dideoxy-ATP. Studies with kinase-deficient mutant CEM lines indicate, however, that 2'-F-dd-ara-A favors a more direct anabolic route toward formation of 2'-fluoro-dideoxynucleotides, catalyzed initially by 2'-deoxycytidine kinase. In MOLT-4 cells, amounts of 2'-fluoro-dideoxyarabinosyladenine di- and triphosphate formed were approximately 20-fold and 5-fold greater than the respective accumulation of 2',3'-dideoxy-ADP and 2',3'-dideoxy-ATP over the same time of exposure. This metabolic profile was supported by enzymological studies, which revealed that 2'-F-dd-ara-A is deaminated 10 times less rapidly than ddAdo and that the resulting deaminated product is resistant to hydrolysis by purine nucleoside phosphorylase. Under similar conditions, ddAdo was rapidly degraded through cleavage of its deamination product ddlno. Like ddAdo, 2'-F-dd-ara-A was found to be transported by passive diffusion and does not enter cells via the purine nucleoside transport carrier system. However, the rate of entry of 2'-F-dd-ara-A was about half that of ddAdo (9.7 pmol/10(6) cells/min for 2'-F-dd-ara-A versus 18.4 pmol/10(6) cells/min for ddAdo). This investigation, therefore, demonstrates that, under the conditions studied, 2'-F-dd-ara-A and its deamination product 2'-fluoro-2',3'-dideoxyarabinosylhypoxanthine have metabolic properties that differ significantly from those of their parent compounds ddAdo and ddlno. These properties, combined with the previously reported resistance of the fluorinated nucleosides to acid degradation, make these compounds interesting candidates for further study as orally administered agents for the inhibition of human immunodeficiency virus replication in patients with acquired immunodeficiency syndrome.
AMP Deaminase↗
Synthesis and anti-HIV activity of various 2'- and 3'-substituted 2',3'-dideoxyadenosines: a structure-activity analysis.
A systematic synthesis was undertaken of 2',3'-dideoxyadenosine analogues with either an azido, fluorine, or hydroxyl group substituted in the "up" or "down" position of C-2 or C-3 of the sugar moiety. The compounds were evaluated against the cytopathogenicity of human immunodeficiency virus (HIV) for MT-4 cells. The four azido derivatives 6, 7, 8, and 9 were synthesized by a nucleophilic displacement reaction with lithium azide on the mesylates 3, 2, 5, and 4. (Diethylamido)sulfur trifluoride was used for the synthesis of 10-12. The compound 13 was obtained by 2'-deoxygenation of 9-(3-fluoro-3-deoxy-beta-D-xylofuranosyl)adenine. Among the azido derivatives, compound 8 with the 3'-azido "down" was slightly more active than 2',3'-dideoxyadenosine (1) but considerably more toxic, and, of the fluorine series, compound 11, with the 2'-fluoro "up", was the most selective inhibitor of HIV, although it was less active than 1. Hence, none of the newly synthesized compounds proved more selective in their anti-HIV activity than the parent compound, 1.
Antiviral Agents↗
Electrochemical radiofluorination. Part 2. Anodic monofluorination of substituted benzenes using [18F]fluoride.
Electrochemical fluorination of various monosubstituted aromatic compounds was performed with [18F]fluoride using potentiostatic anodic oxidation on platinum electrodes in an undivided cell in acetonitrile with a mixture of Et(3)N.3HF/Et(3)N.HCl as electrolyte. Maximum radiochemical yields were obtained after a charge of 50C passed the solution. The results showed a clear dependence of the radiochemical yields on the oxidation potentials E(1/2) of the substrates as a consequence of different substituents namely CH(3)CO-, F-, Cl-, Br- and tert.-Butyl. With increasing E(1/2), the fluorination yields decreased from 7.9% (tert.-butylbenzene) to 1.5% (acetophenone). The ratio between F-for-X substitution and F-for-H substitution correlated with the bond energies of the C-X bond. With higher bond energies, less X-substitution was observed.
Benzene↗