Fluoro Atom Research Articles

Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC50 values of 1.04±0.11μM, 0.02±0.01μM and 9.11±0.55μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC50 values: 0.64±0.26μM, 0.39±0.11μM, 9.47±0.22μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.

Design and Synthesis of New α-Naphthoflavones as Cytochrome P450 (CYP) 1B1 Inhibitors To Overcome Docetaxel-Resistance Associated with CYP1B1 Overexpression.

CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking α-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-α-naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3') on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble α-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel-resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new α-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics.

Pyridine-enabled copper-promoted cross dehydrogenative coupling of C(sp2)-H and unactivated C(sp3)-H bonds.

The pyridine-enabled cross dehydrogenative coupling of sp2 C-H bonds of polyfluoroarenes and unactivated sp3 C-H bonds of amides was achieved via a copper-promoted process with good functional group compatibility. This reaction showed great site-selectivity by favoring the sp2 C-H bonds ortho to two fluoro atoms of arenes and the sp3 C-H bonds of α-methyl groups over those of the α-methylene, β- or γ-methyl groups of the aliphatic amides. Mechanistic studies revealed that sp3 C-H bond cleavage is an irreversible but not the rate-determining step, and the sp2 C-H functionalization of arenes appears precedent to the sp3 C-H functionalization of amides in this process.

Synthesis and Photovoltaic Properties of Quinoxaline-Based Semiconducting Polymers with Fluoro Atoms

A new accepter unit, 6,7-difluoro-2,3-dihexylquinoxaline, was prepared and utilized for the synthesis of the conjugated polymers containing electron donor-acceptor pair for OPVs. New series of copolymers with dioctyloxybenzodithiophene as the electron rich unit and 6,7-difluoro-2,3-dihexylquinoxaline as the electron deficient unit are synthesized. The solid films of poly[2,6-(4,8-bis(2-ethylhexyloxy)benzo[1,2-b:4,5-b']dithiophene)-alt-5,8-(6,7-difluoro-2,3-dihexylquinoxaline)] (PBQxF) and poly[2,6-(4,8-bis(2-ethylhexyloxy) benzo[1,2-b:4,5-b']dithiophene)-alt-5,8-(6,7-difluoro-2,3-dihexyl-5,8-di(thiophen-2-yl) quinoxaline)] (PBDTQxF) show absorption bands with maximum peaks at about 599 and 551 nm and the absorption onsets at 692 and 713 nm, corresponding to band gaps of 1.79 and 1.74 eV, respectively. The devices comprising PBQxF with <TEX>$PC_{71}BM$</TEX> (1:2) showed open-circuit voltage (<TEX>$V_{OC}$</TEX>) of 0.64 V, short-circuit current density (<TEX>$J_{SC}$</TEX>) of <TEX>$1.58mA/cm^2$</TEX>, and fill factor (FF) of 0.39, giving power conversion efficiency (PCE) of 0.39%. To obtain absorption in the longer wavelength region, thiophene units without any alkyl group are incorporated as one of the monomers in PBDTQxF, which may result in low solubility of the polymers to lead lower efficiency.

Phosphonic acid derivatives used in self assembled layers against metal corrosion

The preparation of self assembled molecular(SAM) layers needs molecules with a small hydrophilic and a big hydrophobic molecular parts. Special molecules were chosen where the head group was in all cases phosphonic group, but there were significant differences in the other molecular part. In one case a medium sized carbon chain with a single double bound, in the second case a long alkyl chain with fluoro atoms, and in the third case a polymer molecular part represented the hydrophobic molecular section. Our work was focused on the preparation and characterization of their SAM layers they formed on solid surfaces under the different conditions. The molecular films were deposited from organic solvents on different metal surfaces covered by oxide layer. In the case of the layer with double bounds, polymerization of the molecules on the surface with UV light was applied. The modified surfaces were characterized by the wettability and their anti-corrosion activity was determined in linear polarization experiments. According to the numerical results the wettability of the surfaces differed significantly, i.e., we successfully modify the solid surface with the coatings. The anti-corrosion activity of the coated surfaces depends on the molecules used for layer deposition. The samples with fluoro-alkyl chains gave the best results, not only their contact angles were very high but their anti-corrosion effectiveness was the best.

An expression system for the efficient incorporation of an expanded set of tryptophan analogues

Biosynthetic incorporation of tryptophan (Trp) analogues in recombinant proteins using an E. coli Trp auxotroph expression host is limited to analogues modified with a small substituent like a fluoro atom or a hydroxyl or amine group. We report here the efficient incorporation (>89%) of chloro- and bromo atoms containing Trp analogues in alloproteins at high expression levels using a Lactococcus lactis Trp auxotroph strain. This result was only obtained after coexpression of the enzyme tryptophanyl-tRNA synthetase (TrpRS) of L. lactis, an enzyme believed to show a more relaxed substrate specificity than TrpRS from E. coli. Chloro- and bromo-Trps are attractive intrinsic phosphorescence probes as these Trp analogues are much less sensitive for quenchers in the medium, like oxygen, than Trp. Coexpression of TrpRS was also essential for the biosynthetic incorporation (94%) of the Trp analogue 5,6 difluoroTrp. This makes our expression system ideally suited to generate a set of methyl- and fluoro-substituted Trp analogue-containing alloproteins in high yield for investigating the involvement of the Trp residue in cation-pi or pi-pi interactions. Taken together, the presented Trp auxotroph expression system features the most relaxed specificity for Trp analogue structures reported to date and gives a high alloprotein yield.

Conjugated polymers with 2,7-linked 3,6-difluorocarbazole as donor unit for high efficiency polymer solar cells

A novel donor–acceptor (D–A) copolymer PDFCDTBT with 3,6-difluoro substituted carbazole as the donor unit and dialkoxy substituted benzothiadiazole as the acceptor unit has been synthesized and used as a donor material for bulk heterojunction polymer solar cells (BHJ PSCs). PDFCDTBT possesses a band gap of 1.75 eV, a low-lying HOMO energy level of −5.23 eV, and a good thermal and electrochemical stability. In comparison with the corresponding non-fluoro substituted HXS-1, which has a HOMO energy level of 5.21 eV, a LUMO energy level of 3.35 eV, and an optical band gap of 1.86 eV, the incorporation of two fluoro atoms in the carbazole donor unit lowers the HOMO and the LUMO energy levels of the polymer, which results in simultaneously decreasing the band gap of the polymer and increasing the Voc of polymer solar cells. The fluoro-containing polymer PDFCDTBT also shows strong intramolecular interactions and forms close packing in the solid state. Polymer solar cells based on PDFCDTBT and (6,6)-phenyl-C71-butyric acid methyl ester (PC71BM) demonstrate a power conversion efficiency (PCE) of 4.8% with a Voc of 0.91 V, a Jsc of 9.5 mA cm−2, and an FF of 0.55. In comparison with HXS-1, the better stability, higher Voc, and narrower band gap indicate that PDFCDTBT is a very promising donor material for high efficiency polymer solar cells.

Modified Diblock Copolymer Bearing Fluoro Groups and Evaluation of its Hydrophobic Properties

AbstractSummary: The major scope of the presented work is the characterization and evaluation of hydrophobicity of novel copolymers of the PS‐b‐PB1,2 type, modified with perfluorooctanoyl chloride [PS: polystyrene, PB1,2: poly(butadiene) with 100% 1,2‐microstructure]. Fluoro atoms in polymers can create hydrophobic surfaces with low surface energy. The fluorinated groups can migrate and possible orient in the outermost surface of the polymeric thin film. Characterization in the modified block copolymer was conducted with carbon nuclear magnetic resonance (13C‐NMR) and thermogravimetric analysis (TGA) to evaluate the structure. Contact angle measurements were also conducted to verify the hydrophobicity of the fluorinated copolymer. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to depict the structure of the material. The obtained results showed that indeed the fluorinated copolymer exhibits high hydrophobicity (low surface energy material) with significant structural differences from its precursor.

Electronic Effect of Fluoro Substituents on Chromium(III) Complexes bearing β-Diketiminate Ligands for Ethylene Polymerization

A series of new chromium(III) complexes bearing fluoro-substituted β-diketiminate ligands have been synthesized and characterized by IR and elemental analyses. When activated by modified methylaluminoxane (MMAO), these Cr complexes exhibited moderate or high activities for ethylene polymerization (up to 370 g.mmol-1.h-1). Various reaction parameters such as reaction temperature and Al/Cr ratio were investigated in detail. Further more, it was found for the first time that the catalytic behaviors of Cr complexes can be greatly influenced by the electronic effect of fluoro substituents. The introduction of electron-withdrawing fluoro groups to ligands can improve the catalytic performances compared with those bearing alkyl groups, but incorporation of more fluoro atoms would then decrease the catalytic activities.

Capturing a Synergistic Effect of a Conical Push and an Inward Pull in Fluoro Derivatives of Li@B10H14 Basket: Toward a Higher Vertical Ionization Potential and Nonlinear Optical Response

We present the design of fluoro derivatives of B(10)H(14) and Li@B(10)H(14) baskets. A synergistic effect of conical push and inward pull (reported independently in previous lithium nonlinear optical (NLO) complexes) has been explored in these derivatives to achieve a robustly large NLO response and a higher vertical ionization potential. Li@1,3,6,9-F(4)B(10)H(10), Li@6,9-F(2)B(10)H(12), and Li@2,4,6,9-F(4)B(10)H(10) exhibit first hyperpolarizability (β(0)) values as large as 181 624, 133 199, and 32 314 au; their vertical ionization potentials are 6.45, 6.30, and 6.78 eV, respectively. These values are significantly higher than those previously reported in Li-doped fluorocarbon chains at the same MP2/6-31+G* level of theory (Xu, H. L.; Li, Z. R.; Wu, D.; Wang, B. Q.; Li, Y.; Gu, F. L.; Aoki, Y. J. Am. Chem. Soc. 2007, 129, 2967). They also exceed those from our earlier designed Li@B(10)H(14) basket (Muhammad, S.; Xu, H. L.; Liao, Y.; Kan, Y. H.; Su , Z. M. J. Am. Chem. Soc. 2009, 131, 2967). In addition, new quantum chemical calculations of enthalpies of reaction (Δ(r)H°) at 298 K for B(10)H(14) and its lithium/fluoro derivatives highlight the changes in their thermodynamical aspects. The calculated enthalpies of lithiation reactions are -10.04, -11.29, and -13.18 kcal/mol for B(10)H(14), 6,9-F(2)B(10)H(12), and 2,4-F(2)B(10)H(12), respectively, demonstrating a higher probability of fluoro decaboranes for reaction with lithium. The obtained results not only explain the effect of position and number dependence of substituted fluoro atom(s) in B(10)H(14) and Li@B(10)H(14) but also elucidate a synergistic behavior to polarize a lithium excess electron for high NLO responses and vertical ionization potentials.

Fluoroquinolones as potential photochemotherapeutic agents: covalent addition to guanosine monophosphate

The triplet aryl cation photochemically generated from fluoroquinolones bearing a fluoro atom at position 8 attacks guanosine monophosphate (k(r) > 10(9) M(-1)s(-1)) and forms covalent adducts. The reaction is a model for the implementation of oxygen-independent photochemotherapy.

Influence of Backbone Fluorine Substitution upon the Folding Equilibrium of a β-Heptapeptide

Explicit solvent molecular dynamics (MD) simulations of three beta-heptapeptides with a central beta- HAla(alpha-F) amino acid (Figure 1) in methanol are reported. They aim at an analysis of the conformational consequences of C(alpha) carbon atom bound fluoro atoms, and the particular configuration of the central fluoro-beta-amino acid: peptide 3 with an S configuration of the C(alpha) bound fluor atom, peptide 4 with an R configuration of the C(alpha) bound fluor atom, and peptide 5 with a difluoro substitution at the C(alpha) atom of residue 4. The NMR and CD spectra of these three beta-peptides were earlier (Mathad et al. Helv. Chim. Acta 2005, 88, 266-280) interpreted to indicate a decrease in propensity of 3(14)-helical structure from peptide 4 to peptide 5 to peptide 3. This result was at odds with previous experimental data for beta-heptapeptides with a central beta-HAla(alpha-Me) amino acid which showed that the beta-heptapeptide with the S,S configuration of the central beta-HAla(alpha-Me) was the most 3(14)-helical, whereas the S,R configuration did not lead to any detected helicity. The reported MD simulations resolve this paradox. The MD trajectories of all three peptides do agree with the primary, measured data: NMR nuclear Overhauser effect (NOE) atom-atom distance bounds and (3)J-coupling constants. A conformational analysis of the MD trajectory conformations shows, however, a decrease in 3(14)-helical character from peptide 3 to peptide 5 to peptide 4, which is in line with the results for the nonfluorinated peptides. It is shown that interpretation of NMR NOE data using single-structure refinement in vacuo based on local (along the sequence) and limited atom-atom distance data as in ref 1 (Mathad et al. Helv. Chim. Acta 2005, 88, 266-280) may lead to molecular structures that are not representative for the ensemble of molecular conformations.

Highly Fluorinated Dithieno[3,2-b:2′,3′-d]phospholes with Stabilized LUMO Levels

A series of dithieno[3,2-b:2′,3′-d]phospholes with a perfluorophenyl substituent at the phosphorus center has been synthesized. Further cross-coupling reactions with additional fluorinated phenyl groups afforded extended conjugated materials with different substitution patterns. Investigation of the optoelectronic properties of the materials revealed smaller highest occupied molecular orbital (HOMO)−lowest unoccupied molecular orbital (LUMO) gaps for the extended materials that were also confirmed by theoretical density functional theory (DFT) calculations. These further indicated that the LUMO levels experience a more significant drop in energy than the respective HOMO levels. This fact can be attributed to the strongly electron-withdrawing nature of the fluoroaryls. In addition, the absolute energies of the frontier orbitals depend on the position of the fluoro substituents in the terminal aryl groups, with meta-positioned fluoro atoms having the strongest effect. Electrochemical investigations as well ...

First synthesis and further functionalization of 7-chloro-imidazo[2,1- b][1,3]thiazin-5-ones

A convenient four-step preparation route to novel 7-chloro-imidazo[2,1- b][1,3]thiazin-5-ones is presented, starting from methyl phenylglyoxylate. A unique feature of this synthesis is a heterocyclization strategy, in which a halogen atom is introduced already during the ring closure. 7-Chloro-6-phenyl-imidazothiazinones with a broad range of various substituents in the phenyl and imidazole moieties are obtainable by this method, as well as different chlorinated triazolothiazinones. The chloro function can be easily replaced in nucleophilic substitution reactions by amino, alkoxy and arylthio groups as well as by a fluoro atom.

Synthesis and Evaluation of 7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as Potassium-Competitive Acid Blockers

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R3, R6, and Ar on the biological activity and the physicochemical properties of the target compounds was examined. In contrast to the parent system (R6 = H), compounds in which R6 represents a carboxamide residue generally show improved in vivo activity and favorable pKa/log D values. Whereas variation of R3 is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for R3 = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.

Synthesis and SAR of [1,2,4]Triazolo[1,5-a]pyrimidines, a Class of Anticancer Agents with a Unique Mechanism of Tubulin Inhibition

The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel.1 Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously.

Synthesis of Fluorofurazans

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Synthesis of fluorofurazans

Furazans bearing fluoro atoms are easily obtained by nucleophilic displacement of a nitro group at the furazan ring upon treatment with TEAHF in a solution of [BMIM][BF 4 ].

Peptidyl Prolyl cis/trans-Isomerases: Comparative Reactivities of Cyclophilins, FK506-Binding Proteins, and Parvulins with Fluorinated Oligopeptide and Protein Substrates

Peptidyl prolyl cis/trans-isomerases catalyze the cis-trans isomerization of prolyl bonds in oligopeptides and various folding states of proteins. The proline residue in PPIase substrates at the P1' subsite, which follows the isomerizing peptide bond, appears to be the common recognition element for all subfamilies of this enzyme class. The molecular principles that govern substrate specificity at the P1' subsite were analyzed using 4-fluoroproline-containing tetrapeptide 4-nitroanilides and barstar Cys40Ala/Cys82Ala/Pro27Ala/Pro48-->4-fluoroproline quadruple variants. Generally, PPIase catalysis demonstrated stereospecificity for monofluoro substitutions at the 4-position of the pyrrolidine ring. However, the replacement of hydrogens with fluoro atoms did not impair productive interactions for the majority of PPIase-substrate complexes. Comparison of specificity constants for oligopeptide and protein substrates revealed striking differences in the 4-fluoroproline substituent effects between members of the PPIase families. Introduction of 4(R)-fluoroproline resulted in an oligopeptide substrate completely resistant to catalytic effects of FKBP-like PPIases. By contrast, the 4(R)-fluoroproline barstar variant demonstrated only slightly reduced or even better catalytic susceptibility when compared to the parent barstar Cys40Ala/Cys82Ala/Pro27Ala/Pro48 substrate. On the other hand, Suc-Ala-Ser-4(S)-FPro-Phe-pNA exhibits a discriminating specificity toward the prototypic parvulin, the Escherichia coli Par10. The E. coli trigger factor, in the extreme, catalyzes Cys40Ala/Cys82Ala/Pro27Ala/4-F(2)Pro48 with a more than 20-fold higher efficiency when compared to the proline-containing congener. These findings support the combined subsite concept for PPIase catalysis in which the positioning of a substrate in the active cleft must activate a still unknown number of remote subsites in the transition state of the reaction. The number of critical subsites was shown to vary between the PPIase families.

In vivo synthesized proteins with monoexponential fluorescence decay kinetics.

Tryptophan, when in a protein, typically shows multiexponential fluorescence decay kinetics. Complex kinetics prevents a straightforward interpretation of time-resolved fluorescence protein data, particularly in anisotropy studies or if the effect of a dynamic quencher or a resonance energy transfer (RET) acceptor is investigated. Here, time-resolved fluorescence data are presented of an isosteric tryptophan analogue, 5-fluorotryptophan, which when biosynthetically incorporated in proteins shows monoexponential decay kinetics. Data are presented indicating that the presence of a fluoro atom at the 5-position suppresses the electron transfer rate from the excited indole moiety to the peptide bond. This process has been related to the multiexponential fluorescence decay of tryptophan in proteins. The monoexponential decay of 5-fluorotryptophan makes it possible to measure simultaneously multiple distances between 5-fluorotryptophan and a RET acceptor. We demonstrate that for an oligomeric protein, consisting of two single-tryptophan-containing subunits, the individual distances between 5-fluorotryptophan and the single substrate binding site can be resolved using a substrate harboring a RET acceptor.