Fluoro Groups Research Articles

The critical role of novel benzophenone analogs on tumor growth inhibition targeting angiogenesis and apoptosis.

In modern biology, one of the major topics of importance is progress in anti-cancer drugs with specific targets. The angiopreventive and in vitro tumor inhibition activities of novel synthetic benzophenone analogs have been investigated intensively and explored in a very systematic way. Novel benzophenone analogs (9a-d and 10a-d) substituted with methyl, chloro and fluoro groups at different positions on an identical chemical backbone and incorporating variations in the number of substituents have been synthesized in a multistep process and characterized. In this study, we further evaluate the newly synthesized compounds for their cytotoxic and anti-proliferative effects against A549, HeLa and MCF-7 cells. The potent lead compound was further assessed for anti-angiogenic effects. Through the structure-activity relationship, we found that an increase in the number of methyl, chloro and fluoro groups in a benzophenone ring on compound 9d resulted in higher potency compared to other compounds. Tumor inhibition was notably promoted, and this was reflected in effects on neovessel formation in in vivo systems, such as the CAM. Compound 9d interacts with rVEGF through hydrogen bonds in silico, thereby down-regulating the expression of VEGF in angiogenesis. From our investigation, it is suggested on the basis of clonogenesis and cell migration assays that compound 9d has the potency to exhibit prolonged activity against cancer progression, through cell cycle arrest at the G2/M phase. In addition, compound 9d inhibits A549 cells through caspase-activated DNase-mediated apoptosis.

Determination of Fragmentation Schemes and Metabolites of Fluorinated Histone Deacetylase Inhibitors for Use as Positron Emission Tomography Imaging Agents Using HPLC-MS/MS

High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.

Pentacoordinated Chloro-Iron(III) Complexes with Unsymmetrically Substituted N2O2 Quadridentate Schiff-Base Ligands: Syntheses, Structures, Magnetic and Redox Properties

Since their development in the 1930s, Schiff-base complexes have played an important role in the field of coordination chemistry. Here, we report the synthetic, spectral, structural, magnetic and electrochemical studies of two new pentacoordinated neutral chloro-iron(III) complexes (3,5) supported by dianionic [N2O2]2− tetradentate Schiff-base ligands unsymmetrically substituted by either a pair of acceptor (F and NO2) or donor (ferrocenyl and OCH3) groups. The electron-withdrawing Schiff-base proligand 2 and the complexes 3 and 5 were prepared in good yields (79–86%). Complex 3 was readily obtained upon reaction of 2 with anhydrous iron chloride under basic conditions, while the bimetallic derivative 5 was synthesized by condensation of the free amino group of the ferrocenyl-containing O,N,N-tridentate half-unit 4 with 5-methoxysalicylaldehyde in the presence of FeCl3. The three new compounds were characterized by elemental analysis, FT-IR, UV–Vis, mass spectrometry and in the case of 2 by multinuclear NMR spectroscopy. The crystal structures of 3 and 5 revealed that in the two five-coordinate monomers, the iron atom showed distorted square-pyramidal geometry, with the N and O atoms of the Schiff-base ligand occupying the basal sites and the chlorine atom at the apex of the pyramid. Magnetic measurements showed a high-spin configuration (S = 5/2) for the Fe(III) ion in 3 and 5. Reduction associated with the Fe(III)/Fe(II) redox couple occurred at −0.464 and −0.764 V vs. Ag/Ag+, and oxidation taking place at the Schiff-base ligand was observed at 1.300 and 0.942 V vs. Ag/Ag+ for 3 and 5, respectively. A high-electronic delocalization of the Schiff-base ligand substituted by fluoro and nitro groups stabilizes the Fe(II) oxidation state and shifts the redox potential anodically.

Systematic Engineering of Single Substitution in Zirconium Metal-Organic Frameworks toward High-Performance Catalysis.

Zirconium-based metal-organic frameworks (Zr-MOFs) exhibit great structural tunability and outstanding chemical stability, rendering them promising candidates for a wide range of practical applications. In this work, we synthesized a series of isostructural PCN-224 analogues functionalized by ethyl, bromo, chloro, and fluoro groups on the porphyrin unit, which allowed us to explicitly study the effects of electron-donating and electron-withdrawing substituents on catalytic performance in MOFs. Owing to the different electronic properties of ethyl, bromo, chloro, and fluoro substitutes, the molecular-level control over the chemical environment surrounding a catalytic center could be readily achieved in our MOFs. To investigate the effects of these substitutes on catalytic activity and selectivity, the oxidation of 3-methylpentane to corresponding alcohols and ketones was utilized as a model reaction. Within these five analogues of PCN-224, an extremely high turnover number of 7680 and turnover frequency of 10 240 h-1 was achieved by simply altering the substitutes on porphyrin rings. Moreover, a remarkable 99% selectivity of the tertiary alcohol over the five other possible by-products are realized. We demonstrate that this strategy can be used to efficiently screen a suitable peripheral environment around catalytic cores in MOFs for catalysis.

Oxidative Homocoupling Reaction of Aryltrimethylsilanes by Pd/o-Chloranil Catalysis

A practical oxidative homocoupling reaction of aryltrimethylsilanes has been achieved by Pd/o-chloranil catalytic system. The reaction shows the good functional group tolerability toward bromo, fluoro, ester, and methoxy groups to give a series of biaryls bearing electron-withdrawing and -donating groups. The boronate group is also retained on biaryls without any Ar–B bond cleavage, which is highly advantageous for orthogonal coupling.

Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13

An expeditious route to fused triazolo-pyrido benzoxazepines has been developed using flow and microwave-mediated cyclization chemistry. A range of substituted aryl hydrazides are coupled with a core chloroimine in good to excellent yield via a Pellizzari type process, producing 1,2,4-triazolo-pyrido [2,3-b] [1,5] benzoxazepines with structural similarity to known antipsychotic agents. Modifications allow for strategically functionalized derivatives, and installation of a fluoro group for use in PET imaging is also demonstrated. Given the affinity of the tricyclic core for 5-HT and dopamine receptors, the derivatives are expected to find utility in CNS research.

Optical limiting of germanium(IV) and tin(IV) phthalocyanines in solution and polymer matrices and comparison to an indium(III) phthalocyanine

A series of peripheral and axial substituted germanium(IV) and tin(IV) phthalocyanines substituted by fluoro, chloro, nitro or phenoxy groups were prepared and characterized by their absorption spectra in solution and in polymer matrices. Multi-layer films of PMMA and PVC containing monomolecular Ge(IV) or Sn(IV) phthalocyanines were obtained by spin-coating from solution on glass plates. Optical limiting properties of these phthalocyanines in solution and in polymer films were investigated using the Z-scan technique at 532 nm. A known indium(III) phthalocyanine was also investigated to compare its optical limiting behavior with the Ge(IV) and Sn(IV) containing compounds. Ge(IV) and Sn(IV) phthalocyanines exhibit a better optical limiting performance in polymer matrices than in solution, which is interesting for practical applications.

Synthesis and characterization of some novel 4-arylglyoxal-chromene derivatives in the presence of a polymeric catalyst and biological evaluation against Escherichia coli

A poly(N-vinylimidazole)-catalyzed one-pot multicomponent reaction for the synthesis of 2-amino-4H-benzo[g]chromenes containing acyl group on the 4H-chromene ring has been developed. The products were obtained in generally good to excellent yields in the presence of low loading of poly(N-vinylimidazole) as a reusable basic catalyst via this synthetic strategy. Importantly, the catalyst has the unique ability of being easily separated and recycled. The products were screened for their antibacterial activity against Escherichia coli. The results of antibacterial studies showed that three 4-aroylchromene derivatives completely inhibited E. coli at 32 mg cm−3, whereas other derivatives were either moderately active or inactive up to 64 mg cm−3. Highest antimicrobial activity was observed when the phenylglyoxal hydrate was substituted with fluoro, nitro, and methoxy groups at para position.

Synthesis and mesomorphic properties of calamitic shaped molecules with chalconyl-ester and lateral fluoro substituents

GRAPHICAL ABSTRACT

Synthesis of Fluorine-Containing Tetraarylanthracenes via Ruthenium-Catalyzed C–O or C–F Arylation and their Crystal Structures

Tetraarylanthracenes containing several fluoro groups were synthesized using the ruthenium-catalyzed C–O or C–F arylation with arylboronates and their structural and spectroscopic studies were conducted. The RuH2(CO)(PPh3)3-catalyzed C–O arylation of aromatic ketones was found to be effective for the introduction of aryl groups containing multiple fluoro groups. Anthracenes possessing fluorinated aryl groups were prepared in two steps from 1,4,5,8-tetramethoxyanthraquinone by C–O arylation and reduction of the carbonyl groups. A tetraphenylanthracene containing a fluorinated anthracene moiety was also prepared using C–F phenylation of octafluoroanthraquinone. Single-crystal X-ray diffraction analysis showed that the positions of fluoro groups on the tetraarylanthracenes lead to notable difference in the crystal packing structures. The larger difference between the tetraarylanthracenes was observed in the fluorescence spectra in the solid state than those in chloroform.

Palladium-Catalyzed Decarboxylative Coupling of Alkynyl Carboxylic Acids with Aryl Tosylates.

Decarboxylative coupling reactions of alkynyl carboxylic acids with aryl tosylates were developed in the presence of a palladium catalyst. Among the commercially available phosphine ligands, only 1-dicyclohexylphosphino-2-(di-tert–butylphosphino-ethyl)ferrocene (CyPF-tBu) showed good reactivity. The reaction took place smoothly and gave the decarboxylative coupled products in moderate to good yields. This demonstrates the excellent functional group tolerance toward alkyl, alkoxy, fluoro, thiophenyl, ester, and ketone groups. In addition, alkyl-substituted propiolic acids, such as octynoic and hexynoic acids, were coupled with phenyl tosylate to provide the desired products. We found that the electronic properties of the substituents on the phenyl ring in arylpropiolic acids are an important factor. The order of reactivity was found to be aryl iodide > aryl bromide > aryl tosylate > aryl chloride. However, aryl chloride-bearing electron-withdrawing groups showed higher reactivity than those bearing aryl tosylates.

Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as amyloid β-targeted compounds against Alzheimer’s disease

A series of new benzothiazol-based 1,3,4-oxadiazole derivatives were synthesized and evaluated for their neuroprotective effects against Aβ25–35-induced toxicity in SH-SY5Y cells. The bioassay results indicated that most of the tested compounds exhibited promising neuroprotective activity. In particular, compound 2-[[[5-[(4-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole showed the most potent activity (95.7% of cell viability at 10 μM), better than the positive control EGCG (90.7% of cell viability at 10 μM). Furthermore, compounds 2-[[[5-[(2-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, 2-[[[5-[(4-bromo-2-fluorophenylmethylyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, and 2-[[[5-[(4-methoxyphenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole displayed neuroprotective activity similar to EGCG (87.7, 89.1, and 87.7% of cell viability, respectively, at 10 μM). The preliminary SARs analysis indicated that benzene ring is the key factor for the neuroprotective activity and the bromo atom substituted at 4-position of the benzene ring favors the neuroprotective activity. In addition, the fluoro group in the benzene ring appears not beneficial for the neuroprotective activity.

Configurational Stability of [5]Helicenes.

A series of [5]helicenes difunctionalized in the fjord region with either fluoro, methoxy, or methyl groups was synthesized via photochemical and benzylic coupling route. Resolution of each compound into enantiomers and determination of the Gibbs activation energies of enantiomerization (ΔG⧧(T)) revealed high configurational stability in all three cases. The ΔG⧧(T) values of difunctionalized [5]helicenes were compared with those of their monofunctionalized analogues and the parent [5]helicene. Within this series, an exponential correlation between the torsional twist and ΔG⧧(T) was found. The dimethyl derivative exhibits one of the highest configurational stabilities among [n]helicenes reported to date, comparable to that of [9]helicene.

Physicochemical properties of liquid natural rubber bearing fluoro groups for hydrophobic surfaces

The modification of liquid natural rubber (LNR) has attracted interests among chemists as it brings improvements to several of its properties and widens its application to various fields. LNR can be modified into fluorinated LNR (F-LNR) which is of interest to industries due to its remarkable properties, including low surface energies, high thermal stabilities, together with its significant hydrophobic characters. In this work, a new route to prepare fluorinated rubber was presented. Hydroxylated LNR (OH-LNR) was initially synthesized in good yield via oxidation in the presence of tungsten complex catalyst and acetic acid with hydrogen peroxide as an oxidant. The optimum hydroxyl content of 57.0% was obtained within 6 h reaction time at 90 °C. In the second step, the esterification of OH-LNR using pentadecafluorooctanoyl chloride (PDFOC) under mild conditions was conducted, leading to LNR bearing fluoro groups in the side chain of LNR (F-LNR). ATR-FTIR spectroscopy was used to elucidate the structure and determine any changes in the functional groups that may have been induced during the reaction. 1H NMR spectroscopy was employed to reveal that a high fluorine content of 48.6% was obtained using 3:1 molar ratio of OH-LNR:PDFOC for 8 h at 50 °C. The microstructure of F-LNR was further analyzed using 19F NMR and 13C NMR spectroscopies, and the results confirmed the presence of fluorine in LNR. Thermogravimetric analyses also indicated that the modification improved thermal stability of the LNR. Contact angle measurements were also conducted to verify the hydrophobicity of the fluorinated rubber and the results obtained showed that F-LNR exhibited higher hydrophobicity than LNR.

Improvement of the efficiency of dye-sensitized solar cells with fluorinated carbon-based liquid crystal dopant

The long-term stability of dye-sensitized solar cells (DSSCs) can be improved using a liquid crystal (LC) dopant. However, the high viscosity of the LC dopant reduces the power conversion efficiency (PCE) of these cells. In this study, low-viscosity LC is doped into the DSSCs. The results indicate that the polar fluoro groups of the LCs effectively interact with the cyano groups of the organic solvent in the liquid electrolyte, enhancing the long-term stability of the DSSCs. The viscosity of the LC dopant is a key factor that affects the light–to–electrical energy conversion efficiency of the LC-doped DSSCs. The short-current density and related PCE of the DSSCs is not reduced because of the low viscosity of the doped fluorinated carbon-based LCs.

Synthesis of Functionalized 4‐Fluoropyridazines

AbstractA route to 4‐fluoropyridazines by a [2+1]/[3+2] cycloaddition sequence between an acetylenic derivative, a difluorocarbene source, and a diazo compound is reported. This approach is highly modular and compatible with a broad range of functional groups. The protocol does not require the isolation of any reactive intermediates and, thus, allows for access to a wide range of 4‐fluoropyridazines in a single synthetic step from simple alkynes. Furthermore, these fluorinated compounds can be easily diversified by nucleophilic aromatic substitution (SNAr) to displace the fluoro group to give a wider range of 3,4,6‐trisubstituted pyridazines. As a result of increasing interest in functionalized pyridazines as well as fluorinated derivatives, this efficient and concise approach to 4‐fluoropyridazines should be of value to medicinal chemists.

2-Benzamido-4-methylthiazole-5-carboxylic Acid Derivatives as Potential Xanthine Oxidase Inhibitors and Free Radical Scavengers.

The new chemical entities febuxostat and topiroxostat have been approved by the US Food and Drug Administration, opening new avenues for exploiting different heterocycles other than purines as xanthine oxidase (XO) inhibitors. A different series of substituted 2-benzamido-4-methylthiazole-5-carboxylic acid derivatives (5a-r) was synthesized and characterized by the collective use of IR, 1 H and 13 C NMR, and mass spectroscopy, for the treatment of gout and hyperuricemia. In vitro studies of the synthesized derivatives revealed that the presence of a fluoro group at the para position in 5b (IC50 = 0.57 μm) and a chloro group in 5c (IC50 = 0.91 μm) signifies excellent XO inhibitory activity among the series, along with their DPPH free radial scavenging activity. In vivo serum uric acid inhibition studies established that 5b and 5c displayed 62 and 53% uric acid inhibition, respectively. Studies on enzyme kinetics indicated that 5b acts as a mixed type inhibitor. In silico prediction by various softwares also helped in the recognition of potent XO inhibitors.

Synthesis, structure-activity relationships studies of benzoxazinone derivatives as α-chymotrypsin inhibitors

A series of benzoxazinones 1–28 were synthesized via reaction of anthranilic acid with various substituted benzoyl chlorides in the presence of triethylamine in chloroform. Compounds 1–18 showed a good inhibition of α-chymotrypsin with IC50±SEM values between 6.5 and 341.1μM. Preliminary structure-activity relationships studies indicated that the presence of substituents on benzene ring reduces the inhibitory potential of benzoxazinone. Also the increased inhibitory potential due to fluoro group at phenyl substituent was observed followed by chloro and bromo substituents. Compounds with strong electron donating or withdrawing groups on phenyl substituent, showed a good inhibitory potential at ortho>meta>para position. Kinetics studies showed diverse types of inhibition, except uncompetitive-type inhibition. The Ki values ranged between 4.7 and 341.2μM. Interestingly, most of these compounds were non-cytotoxic to 3T3 cell line at 30μM, except compounds 6, 14 and 15. Competitive inhibitors of chymotrypsin are like to inhibit other α-chymotrypsin-like serine proteases due to structural and functional similarities between them. The inhibitors identified during the current study deserve to be further studied for their therapeutic potential against abnormalities mediated by chymotrypsin or other serine protease.

Biological Evaluation of 2, 5-Di (4 Aryloylaryloxy Methyl) - 1, 3, 4-Oxadiazoles Derivatives as Antimicrobial Agents

A series of potential biologically active substituted 2,5-di(4 aryloylaryloxymethyl)-1,3,4-oxadiazoles 9a-j were evaluated for its potential antimicrobial activity comparing with the standard drugs-Streptomycin and Ketoconazole respectively. Compound 9a with fluoro group exhibited highest activity against both gram-positive and gramnegative bacteria. Compounds 9a with fluoro group and 9c with fluoro and bromo showed good activity against antifungal activities.

Radiosynthesis of novel pitavastatin derivative ([18 F]PTV-F1) as a tracer for hepatic OATP using a one-pot synthetic procedure.

Pitavastatin is an antihyperlipidemic agent, a potent inhibitor of 3-hydroxymethyl-glutaryl-CoA reductase, which is selectively taken up into the liver mainly via hepatic organic anion transporting polypeptide 1B1 (OATP1B1). OATP1B1 can accept a variety of organic anions, and previous reports indicated that it is responsible for the hepatic clearance of several clinically used anionic drugs. Therefore, the pharmacokinetics and the hepatic distribution of pitavastatin provide an insight into the function of OATP1B1 in humans. For the development of the in vivo evaluation of OATP1B1 function by positron emission tomography imaging, we designed a novel [18 F]pitavastatin derivative ([18 F]PTV-F1), in which a [18 F]fluoroethoxy group is substituted for the [18 F]fluoro group of [18 F]pitavastatin, with the aim of convenient radiolabeling protocol and high radiochemical yield. In vitro studies suggested that transport activities of PTV-F1 mediated by OATP1B1 and OATP1B3 were very similar to those of pitavastatin and PTV-F1 was metabolically stable in human liver microsomes. In the radiosynthesis of [18 F]PTV-F1 from the tosylate precursor, nucleophilic fluorination and subsequent deprotection were performed using a one-pot procedure. [18 F]PTV-F1 was obtained with a radiochemical yield of 45%±3% (n=3), and the operating time for the radiosynthesis of [18 F]PTV-F1 is very short (30minutes) compared with [18 F]pitavastatin.