Fluorine Analogues Research Articles

Fluorine analogs of dicamba and tricamba herbicides; synthesis and their pesticidal activity

Abstract Fluorine analogs of the dicamba and tricamba herbicides were synthesized. Their herbicide activities were compared with the activities of the pattern herbicides dicamba and tricamba.

Synthesis and Evaluation of 11C- and 18F-Labeled SOAT1 Inhibitors as Macrophage Foam Cell Imaging Agents.

PD-132301, an inhibitor of sterol O-acyltransferase 1 (SOAT1; also known as acyl-coenzyme A:cholesterol acyltransferase-1, ACAT1), is under clinical investigation for numerous adrenal disorders. Radiolabeled SOAT1 inhibitors could support drug discovery and help diagnose SOAT1-related disorders, such as atherosclerosis. We synthesized two radiolabeled SOAT1 inhibitors, [11C]PD-132301 and fluorine analogue [18F]1. Rat biodistribution studies were conducted with both agents and, as the most selective tracer, [11C]PD-132301 was advanced to preclinical positron emission tomography studies in (atherosclerotic) ApoE-/- mice. The uptake of [11C]PD-132301 in SOAT1-rich tissue warrants further investigation into the compound as an atherosclerosis and adrenal imaging agent.

Photovoltaic polymers based on difluoroqinoxaline units with deep HOMO levels

ABSTRACTWe report the synthesis of low bandgap polymers with a difluoroquinoxaline unit by Stille polymerization for use in polymer solar cells (PSCs). A new series of copolymers with 2,3‐didodecyl‐6,7‐difluoro quinoxaline as the electron‐deficient unit and alkyloxybenzo[1,2‐b:4,5‐b′]dithiophene and thiophene as the electron‐rich unit were synthesized. The photovoltaic properties of the devices based on the synthesized polymers revealed that the fluorine atoms at the quinoxaline units aid in decreasing the highest occupied molecular orbital (HOMO) energy levels; this in turn increased the open circuit voltage of the devices. The polymers with long alkyl chains exhibited good solubility that increased their molecular weight, but the power conversion efficiency was low. Efficient polymer solar cells were fabricated by blending the synthesized copolymers with PC71BM, and the PCE increased up to 5.11% under 100 mW cm−2 AM 1.5 illumination. These results demonstrate that the importance of having a control polymer to be synthesized and characterized side by side with the fluorine analogues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1489–1497

Herbicidal and fungistatic properties of fluorine analogs of phenoxyacetic herbicides

Aryloxy fluoroacetic acids 3a-3h – fluorine analogs of phenoxyacetic herbicides 2,4-D, MCPA, 2,4,5-T, and 4-CPA were efficiently synthesized in 29–88% yield, using appropriate phenols and either bromodifluoro- or bromofluoroacetic acid in the presence of sodium hydride as a base and in either dioxane or THF as solvents. Fluorine derivatives of 2,4-D (3a, 3b) show herbicidal activity against three weed species. Parent herbicides 2,4-D, MCPA, 2,4,5-T, 4-CPA, monofluorine derivatives of MCPA (3d) and 2,4,5-T (3f) show fungistatic activity against phytopatogenic fungi species Phytophtora cactorum.

Simultaneous Increase in Open-Circuit Voltage and Efficiency of Fullerene-Free Solar Cells through Chlorinated Thieno[3,4-b]thiophene Polymer Donor

The chlorinated polymer, PBTCl, has been found to be an efficient donor in nonfullerene polymer solar cells (PSCs), which showed a blue-shifted absorbance compared to that of its fluorine analogue (PTB7-th) and resulted in more complementary light absorption with a nonfullerene acceptor, such as ITIC. Meanwhile, chlorine substitution lowered the HOMO level of PBTCl, which increased the open-circuit voltage of the corresponding polymer-based devices. The 2D GIWAXS analysis illustrated that the PBTCl/ITIC blend film exhibited a “face-on” orientation and scattering features of both PBTCl and ITIC, suggesting that the blend of PBTCl and ITIC was phase-separated and formed individual crystalline domains of the donor and acceptor, which promoted charge transfer in the bicontinuous film and eventually elevated the solar energy conversion efficiency. The PBTCl-based nonfullerene PSC exhibited a maximum PCE of 7.57% with a Voc of 0.91 V, which was an approximately 13% increasing in the PCE compared to that of the ...

Using Protein-Confined Proximity To Determine Chemical Reactivity.

Chemical reactivity is essential for functional modification of biomolecules with small molecules and the development of covalent drugs. The reactivity between a chemical functional group of a small molecule and that of a large biomolecule cannot be reliably predicted from the reactivity of the corresponding functional groups separately installed on two small molecules, because the proximity effect on reactivity resulting from the binding of the small molecule to the biomolecule is challenging to achieve by mixing two small molecules. Here we present a new strategy to determine the chemical reactivity of two functional groups in the context of close proximity afforded by proteins. The functional groups to be tested were separately installed at the interface of two interacting proteins in the format of amino acid side chains via the expansion of the genetic code. Reaction of the two functional groups resulted in covalent cross-linking of interacting proteins, readily detectable by gel electrophoresis. Using this strategy, we evolved new synthetases to genetically encode Nε-fluoroacetyllysine (FAcK), an isosteric fluorine analogue of acetyllysine. We demonstrated that fluoroacetamide installed on FAcK, previously thought inert to biological functional groups, actually reacted with the thiol group of cysteine when in proximity. This strategy should be valuable for accurately evaluating chemical reactivity of small molecules toward large biomolecules, which will help avoid undesired side reactions of drugs and expand the repertoire of functional groups to covalently target biomolecules.

Versatile synthesis and biological evaluation of novel 3'-fluorinated purine nucleosides.

A unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3’-fluorinated analogues were constructed from a common 3’-deoxy-3’-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3’-fluororibose purine nucleosides 1–15 and eight 3’-fluororibose 2-chloro/2-aminopurine nucleosides 16–23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3’-fluorine analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3’-fluorine purine nucleoside analogues display potent tumor cell growth inhibition activity at sub- or low micromolar concentration.

Redefinition of thalénite-(Y) and discreditation of fluorthalénite-(Y): A re-investigation of type material from the Österby pegmatite, Dalarna, Sweden, and from additional localities

AbstractUsing type material from the Österby pegmatite in Dalarna, Sweden, the chemical composition and structural parameters of thalénite-(Y) [ideally Y3Si3O10(OH)] were examined by wavelength dispersive spectroscopy electron microprobe (WDS EMP) analysis and single-crystal X-ray diffraction. High contrast back-scatter electron images of the Österby material show at least two generations of thalénite-(Y). The formula of the primary thalénite-(Y) normalized to 11 anions is (Y2.58Dy0.11Yb0.09Gd0.06Er0.06Ho0.02Sm0.02Tb0.02Lu0.02Nd0.01Tm0.01)Σ3.00Si3.01O10F0.97OH0.03. The secondary thalénite-(Y), replacing the primary material, is weakly enhanced in Y and depleted in the lightest and the heaviest rare-earth elements, yielding the formula (Y2.63Dy0.12Yb0.06Gd0.06Er0.05Ho0.02Sm0.02Tb0.02Tm0.01Nd0.01Lu0.01)Σ3.00Si3.01O10F0.98OH0.02. Structural data for thalénite-(Y) from Österby clearly indicate the monoclinic space group P21/n, with a = 7.3464(4), b = 11.1726(5), c = 10.4180(5) Å, β = 97.318(4)°, V = 848.13(7) Å3, Z = 4, which is consistent with previous investigations. The structure was refined from single-crystal X-ray diffraction data to R1 = 0.0371 for 1503 unique observed reflections, and the final chemical composition obtained from the refinement, (Y2.64Dy0.36)Σ3.00F0.987[Si3O10], Z = 4, is in good agreement with the empirical formula resulting from electron microprobe (EMP) analysis. Both techniques reveal a strong dominance of F over OH, which means that the type material actually corresponds to the fluorine analogue. Moreover, new EMP analyses of samples of thalénite-(Y) from an additional seven localities (Åskagen and Reunavare in Sweden; White Cloud and Snow Flake in Colorado, USA; the Guy Hazel claim in Arizona, USA; Suishoyama and Souri in Japan) clearly show the prevalence of F over OH as well. Based on these observations, the Commission on New Minerals, Nomenclature and Classification of the International Mineralogical Association has recommended a redefinition of the chemical composition of thalénite-(Y) to represent the F-dominant species with the ideal formula Y3Si3O10F, as it has historical priority. Consequently, the later described fluorthalénite-(Y) has to be discredited.

The toxicity of the N-hydroxy and 6-hydroxy metabolites of 3,4-dichloropropionanilide does not depend on calcium release-activated calcium channel inhibition.

Each year ~1 billion kg of herbicides are used worldwide to control the unwanted growth of plants. In the United States, over a quarter of a billion kg of herbicides are used, representing 28% of worldwide use. (Kiely, T., Donaldson, D., and Grube, A. [2004]. Pesticide Industry Sales and Usage. 2000 and 2001 Market Estimates. Available at: http://www.epa.gov/pesticides/pestsales/01pestsales/market_estimates2001.pdf. Accessed October 25, 2012.) Propanil (3,4-dichloropropionanilide [DCPA]) is a commonly used herbicide in the United States, with 2-4 million kg applied annually to 2 million acres of crop land. The immunomodulatory effects of DCPA have been well documented, but limited data are available on the effects of its metabolites. (Salazar, K. D., Ustyugova, I. V., Brundage, K. M., Barnett, J. B., and Schafer, R. [2008]. A review of the immunotoxicity of the pesticide 3,4-dichloropropionanalide. J. Toxicol. Environ. Health B Crit. Rev. 11, 630-645.) In mammals, hepatic enzymes metabolize DCPA, resulting in the production of 3,4-dichloroaniline (DCA). Further biotransformation of DCA leads to the production of 6-hydroxy-3,4-dichloroaniline (6OH-DCA) and N-hydroxy-3,4-dichloroaniline (NOH-DCA). We report, for the first time, the immunotoxic effects of DCPA metabolites on T-cell function. Human Jurkat T cells were exposed to varying concentrations of DCPA or its metabolites and assayed for effects on T-cell function. In addition, fluorine analogs of DCPA and DCA were investigated to determine the relative role of chlorine substituents on T-cell immunotoxicity. Here we report that exposure of Jurkat T cells to DCPA and DCA alters IL-2 secretion, nuclear factor of activated T cells (NFAT) activity, and calcium influx. However, exposure to 6OH-DCA and NOH-DCA reduces IL-2 secretion and NFAT activity but has no effect on calcium flux. When both chlorines in DCPA and DCA were substituted with fluorines all effects were abrogated. Our data indicate that metabolites of DCPA have differential effects on T-cell function and the presence of chlorines plays an important role in eliciting these effects.

Allosteric agonists of the calcium receptor (CaR): fluorine and SF5 analogues of cinacalcet

Three selectively fluorinated cinacalcet analogues are prepared and their activity as calcium-sensing receptor (CaR) agonists is assessed. Individual (2R,1'R)-2 and (2S,1'R)-3 fluorocinacalcet diastereoisomers were prepared using the MacMillan asymmetric fluorination reaction. Assays with the recombinant human CaR revealed that both diastereoisomers have a similar potency to each other although slightly lower (75-80%) than that of cinacalcet 1. The SF(5)-cinacalcet analogue 4 was prepared from meta-pentafluorosulfanyl benzyl alcohol and has ~75% agonist activity relative to cinacalcet 1 indicating that the SF(5) group can replace the CF(3) group and retain significant bioactivity.

Reversal of GABA-mediated Inhibition of the Electrically and Potassium Chloride Evoked [3H]-GABA Release from Rat Substantia Nigra Slices by DL-3-Hydroxy-3-Phenyl Pentanamide

The phenyl alcohol amides, DL-2-hydroxy-2-phenyl butyramide (CAS 52839-87-9), DL-3-hydroxy-3-phenyl pentanamide (CAS 131802-69-2, DL-HEPP) and DL-4-hydroxy-4-phenyl hexanamide (CAS 67880-30-2) and their fluorine and chlorine analogs, at a concentration of 100 micromol/L, did not displace [3H]-gamma-aminobutyric acid ([3H]-GABA, CAS 108158-36-7) from GABAA receptors and only weakly displaced [3H]-GABA and [3H]-CGP62349 (CAS 186986-97-0), a GABAB receptor antagonist, from GABAB receptors in rat brain crude synaptic membranes. The electrically and potassium chloride (15 mmol/L) evoked [3H]-GABA release in the presence of DL-HEPP, GABA and GABAB receptor ligands from rat brain substantia nigra (SN) slices was studied. R-Baclofen (CAS 69308-37-8) (10 micromol/L), a GABAB receptor agonist, produced an inhibition of the electrically evoked [3H]-GABA release and this inhibition was blocked by CGP 55845A (CAS 149184-22-5) (10 micromol/L), a GABAB receptor antagonist, but was not affected by DL-HEPP (100 micromol/L). CGP 55845A (10 micromol/L) did not alter the electrically evoked [3H]-GABA release in the absence of baclofen. The addition of DL-HEPP (100 micromol/L) alone did not affect the electrically-evoked release of [3H]-GABA release control, but it was able to significantly reduce the inhibitory effect of GABA (CAS 56-12-2) (10 micromol/L) on [3H]-GABA release evoked both by electrical and potassium chloride stimulation, in the presence of tiagabine (CAS 115103-54-3) (10 micromol/L), a GABA uptake blocker. In three preliminary experiments, bicuculline (CAS 485-49-4) (10 micromol/L) and picrotoxinin (CAS 17617-45-7) (10 micromol/L), two GABAA antagonists, inhibited the electrically evoked release of [3H]-GABA from rat SN slices, and DL-HEPP (100 micromol/L) reversed this inhibition. The mechanism of action of DL-HEPP is not known but, it might act as a negative GABA modulator in rat brain slices.

ChemInform Abstract: Stereoselective Synthesis of α‐Fluorinated Amino Acid Derivatives.

AbstractReview: ca. 30 refs.

Stereoselective Synthesis of α‐Fluorinated Amino Acid Derivatives

AbstractThis account concentrates on our new methodologies for the synthesis of fluorine analogues of amino acids and their derivatives using the Reformatsky‐type reactions of ethyl bromodifluoroacetate and ethyl dibromofluoroacetate with imines promoted by the Wilkinson catalyst. First, we present the rhodium‐catalyzed Reformatsky‐type reaction of ethyl bromodifluoroacetate with imines using diethylzinc for the chemoselective synthesis of α,α‐difluoro‐β‐lactams and non‐cyclized products, 3‐alkylamino‐2,2‐difluorocarboxylates. This reaction was expanded to the asymmetric synthesis of difluoro‐β‐lactams using two types of chiral auxiliaries. To develop another methodology for the synthesis of monofluoro analogues of amino acids and their derivatives, we investigated the reaction of ethyl dibromofluoroacetate with imines using diethylzinc, and found that this Reformatsky‐type reaction proceeded without a rhodium catalyst in diethyl ether to give syn‐α‐bromo‐α‐fluoro‐β‐lactams stereoselectively. Interestingly, by changing the solvent to acetonitrile, the Reformatsky‐type aza‐Darzens products, syn‐2‐fluoroaziridine‐2‐carboxylates, were obtained chemo‐ and stereoselectively.

ChemInform Abstract: Synthesis of Trifluoromethylated Tetrahydropyrans from Ene Reaction Products of Trifluoromethyl Ketones: Synthesis of Fluorine Analogs of a Sesquiterpene.

ChemInform Abstract: Synthesis of Trifluoromethylated Tetrahydropyrans from Ene Reaction Products of Trifluoromethyl Ketones: Synthesis of Fluorine Analogs of a Sesquiterpene.

Fluorine and Rhenium Substituted Ghrelin Analogues as Potential Imaging Probes for the Growth Hormone Secretagogue Receptor

In our effort to create imaging probes targeting the growth hormone secretagogue receptor (GHSR), we now report on the design and synthesis of fluorine and rhenium containing ghrelin analogues through modification of the n-octanoyl Ser-3 side chain. Fluorine analogues were designed whereby the fluorine atom is situated at the terminus of an aliphatic chain using diaminopropionic acid (Dpr) as residue-3. Truncated ghrelin(1-5) and ghrelin(1-14) fluorine-bearing analogues were prepared, the best of which had a 28 nM IC(50) for GHSR. Ghrelin(1-14) analogues were also prepared containing rhenium, as a surrogate metal for technetium-99m, with a cyclopentadienylrhenium tricarbonyl being situated at the terminus of the residue-3 side chain, yielding compounds the best of which had a 35 nM IC(50). This represents a rare case of incorporating rhenium into a peptide structure where the metal complex is required for biological activity. These fluorine and rhenium derivatives demonstrate the ability to modify the Ser-3 side chain of ghrelin in order to create imaging probes for the GHSR.

Docking Studies on a New Human Immodeficiency Virus Integrase−Mg−DNA Complex: Phenyl Ring Exploration and Synthesis of 1H-Benzylindole Derivatives through Fluorine Substitutions

A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been built. It was used to study the binding mode of integrase strand transfer inhibitor 1 (CHI-1043) and other fluorine analogues. Molecular modeling results prompted us to synthesize the designed derivatives which showed potent enzymatic inhibition at nanomolar concentration, high antiviral activity, and low toxicity. Microwave assisted organic synthesis (MAOS) was employed in several steps of the synthetic pathway, thus reducing reaction times and improving yields.

Structures, vibrational spectra, and relative energetics of FC(O)ONO and FC(O)NO2 isomers at DFT and ab initio levels

The structural and vibrational parameters of FC(O)ONO and FC(O)NO2 isomers were examined theoretically using the B3LYP/6-311+G(3df) and CCSD(T)/6-311G(d) methods. Four conformers of FC(O)ONO isomer and one FC(O)NO2 isomer are found here. Among them, the trans–cis and cis–cis FC(O)ONO configuration are new conformers. The energetics were refined with G3//B3LYP and CBS-QB3 calculations. The trans–trans conformer of the FC(O)ONO isomer is found to be the lowest energy structure, with an estimated heat of formation of −104.9 kcal mol−1 at 0 K as determined from CBS-QB3 theory. The next lowest structure is the cis–trans FC(O)ONO lying 1.7 kcal mol−1 above the trans–trans structural form. The highest energy structure is the FC(O)NO2 isomer with a predicted heat of formation of −84.8 kcal mol−1. A comparison of the relative stability of the FCNO3 isomers with the isomers of ClCNO3 shows that the Cl analogues follow the same pattern of stability, as do the F isomers. However, the chlorine isomers are unstable relative to their fluorine analogues.

Effect of fluorine substitution in calix[4]pyrrole: A DFT study

Using density functional theory we investigate the ground-state geometries and electronic structures of calix[4]pyrrole (C4P) and its fluorine analogue (F-C4P). The HOMO–LUMO energy gap of C4P is 5.9 eV and remains nearly the same upon H-by-F replacement (5.7 eV). Fluorine substitution increases both the vertical and adiabatic ionization potentials of C4P by ∼0.8 eV while the electron affinity of either macrocycle is negative thus indicating that the corresponding radical anion in the gas-phase is thermodynamically unstable. It is shown that the topology of the LUMOs of both C4P and F-C4P have important implications for the spherical recognition of halide anions. The simulated IR, NMR, and electronic spectra display important fingerprints for the characterization of these macrocycles.

Strategies for the Labeling of Halogen-Substituted Peroxisome Proliferator-Activated Receptor γ Ligands: Potential Positron Emission Tomography and Single Photon Emission Computed Tomography Imaging Agents

Well-known as an important regulator of lipid metabolism and adipocyte differentiation, the peroxisome proliferator-activated receptor gamma (PPARgamma) also has potential use as a target for antitumor therapy in certain cancers. To develop agents for radionuclide imaging PPARgamma in vivo, we synthesized fluorine, bromine, and iodine-substituted analogs (1-3) of a high-affinity benzophenone-tyrosine PPARgamma ligand; all three analogs retain very high affinity for the PPARgamma receptor. In preparation for the synthesis of these PPARgamma ligands in radiolabeled form, we have synthesized two types of precursors: (a) an aryltributylstannane (9), from which the bromine and iodine-substituted analogs (2 and 3) can readily be prepared by electrophilic destannylation, and (b) three diaryliodonium tosylate derivatives (12a-c), precursors for nucleophilic aromatic fluorination using fluoride ion. Conditions were developed whereby the thiophenyliodonium tosylate (12c) underwent nucleophilic aromatic substitution with fluoride ion, efficiently and in short reaction times, to produce the desired fluorine-substituted target compound 1. These reactions laid the groundwork for producing these three PPARgamma ligands in radiolabeled form; in addition, our use of diaryliodonium ion precursors for aromatic fluorination in this series provides an example that should encourage application of this approach for radiofluorination of more complicated radiopharmaceuticals.

Magnesium Based Ternary Metal Hydrides Containing Alkali and Alkaline‐Earth Elements

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.