Fluorinated Analogues Research Articles

Fluorinated Analogues of Lepidilines A and C: Synthesis and Screening of Their Anticancer and Antiviral Activity.

Starting with fluorinated benzylamines, a series of 2-unsubstituted imidazole N-oxides was prepared and subsequently deoxygenated in order to prepare the corresponding imidazoles. The latter were treated with benzyl halides yielding imidazolium salts, which are considered fluorinated analogues of naturally occurring imidazolium alkaloids known as lepidilines A and C. A second series of oxa-lepidiline analogues was obtained by O-benzylation of the initially synthetized imidazole N-oxides. Both series of imidazolium salts were tested as anticancer and antiviral agents. The obtained results demonstrated that the introduction of a fluorine atom, fluoroalkyl or fluoroalkoxy substituents (F, CF3 or OCF3) amplifies cytotoxic properties, whereas the cytotoxicity of some fluorinated lepidilines is promising in the context of drug discovery. All studied compounds revealed a lack of antiviral activity against the investigated viruses in the nontoxic concentrations.

Feasibility of Developing Radiotracers for MDM2: Synthesis and Preliminary Evaluation of an 18F-Labeled Analogue of the MDM2 Inhibitor SP-141.

Murine double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor protein, is overexpressed in several human cancers. Herein we investigate the feasibility of developing 18F-labeled compounds based on the small molecule inhibitor SP-141 for imaging tumor MDM2 expression levels with positron emission tomography (PET). Three nonradioactive fluorinated SP-141 analogues, 1–3, were synthesized, and their binding to the MDM2 protein was analyzed by surface plasmon resonance (SPR). One of these, a fluoroethoxy analogue, was labeled with fluorine-18 (18F) using 18F-fluorethyl bromide to provide [18F]1 and evaluated in vitro and in vivo. SPR analysis confirmed the binding of the fluorinated analogues to MDM2 at 1.25–20 µM concentrations. Cell uptake studies revealed high uptake (67.5–71.4%/mg protein) and specificity of [18F]1 in MCF7 and HepG2 cells. The uptake of [18F]1 in these cells could be modulated using 100 µM SP-141, potentially reflecting changes in MDM2 expression because of p53 activation by SP-141. [18F]1 exhibited stable uptake and retention in HepG2 tumor xenografts (~3 %ID/g) in vivo, but poor clearance from blood and other normal tissues, yielding low tumor-to-background ratios (<2) at 2 h post injection. Our results suggest that [18F]1 has suboptimal characteristics for in vivo evaluation as a PET tracer for MDM2, but warrant radiolabeling and assessment of the other fluorinated analogues synthesized in this work, 2 and 3, and potentially other molecular scaffolds for developing MDM2 targeted radiotracers.

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.

A Rational Approach to CO2 Capture by Imidazolium Ionic Liquids: Tuning CO2 Solubility by Cation Alkyl Branching.

Branching at the alkyl side chain of the imidazolium cation in ionic liquids (ILs) was evaluated towards its effect on carbon dioxide (CO2 ) solubilization at 10 and 80 bar (1 bar=1×10(5) Pa). By combining high-pressure NMR spectroscopy measurements with molecular dynamics simulations, a full description of the molecular interactions that take place in the IL-CO2 mixtures can be obtained. The introduction of a methyl group has a significant effect on CO2 solubility in comparison with linear or fluorinated analogues. The differences in CO2 solubility arise from differences in liquid organization caused by structural changes in the cation. ILs with branched cations have similar short-range cation-anion orientations as those in ILs with linear side chains, but present differences in the long-range order. The introduction of CO2 does not cause perturbations in the former and benefits from the differences in the latter. Branching at the cation results in sponge-like ILs with enhanced capabilities for CO2 capture.

EF0176 and EF0177 from Enterococcus faecalis V583 are substrate-binding lipoproteins involved in ABC transporter mediated ribonucleoside uptake.

One of the ABC transporter systems in Enterococcus faecalis V583 is encoded by the ef0176-ef0180 gene cluster, which differs from orthologous operons in related bacteria in that it contains two genes putatively encoding substrate-binding proteins (SBPs). These SBPs, EF0176 and EF0177, have previously been identified on the surface of E. faecalis. By phenotypic studies of single and double knockout mutants, we show here that EF0176 and EF0177 are specific for ribonucleosides and, by inference, that the EF0176-EF0180 ABC transporter plays a role in nucleoside uptake. The specificity of the SBPs was mapped using growth experiments on a medium, RPMI 1640, that only supports growth of E. faecalis when supplemented with purine nucleosides or their corresponding bases. This analysis was complemented by studies with toxic fluorinated pyrimidine ribonucleoside analogues and competition experiments. The data show that EF0176 and EF0177 have broad and overlapping, but not identical, substrate specificities and that they, together, are likely to bind and facilitate the transport of all common ribonucleosides. Comparative sequence analysis and inspection of an available crystal structure of an orthologue, PnrA from Treponema pallidum, showed that the strongest binding interactions between the protein and the ligand involve the ribose moiety and that sequence variation in the binding site primarily affects interactions with the base. This explains both the broad substrate specificity of these binding proteins and the observed variations therein. The presence of two SBPs in this nucleoside ABC transporter system in E. faecalis may improve the bacterium's ability to scavenge nucleosides.

Influence of Fluorination on the Thermodynamics of Protein Folding

The introduction of highly fluorinated analogues of hydrophobic amino acid residues into proteins has proved an effective and general strategy for increasing protein stability toward both chemical denaturants and heat. However, the thermodynamic basis for this stabilizing effect, whether enthalpic or entropic in nature, has not been extensively investigated. Here we describe studies in which the values of ΔH°, ΔS°, and ΔCp° have been determined for the unfolding of a series of 12 small, de novo-designed proteins in which the hydrophobic core is packed with various combinations of fluorinated and non-fluorinated amino acid residues. The increase in the free energy of unfolding with increasing fluorine content is associated with increasingly unfavorable entropies of unfolding and correlates well with calculated changes in apolar solvent-accessible surface area. ΔCp° for unfolding is positive for all the proteins and, similarly, correlates with changes in apolar solvent-accessible surface area. ΔH° for unfolding shows no correlation with either fluorine content or changes in apolar solvent-accessible surface area. We conclude that conventional hydrophobic effects adequately explain the enhanced stabilities of most highly fluorinated proteins. The extremely high thermal stability of these proteins results, in part, from their very low per-residue ΔCp°, as has been observed for natural thermostable proteins.

Synthesis of fluorine substituted pyrazolopyrimidines as potential leads for the development of PET-imaging agents for the GABA A receptors

Neuroimaging of GABA A receptors offers the potential for a better diagnosis of diseases related to a dysfunction of the GABAergic neurotransmission. A series of potent fluorinated analogues of the pyrazolopyrimidine Indiplon has been synthesized and evaluated in vitro as potential agents for imaging the GABA A receptor by means of positron emission tomography (PET). The most promising compound N-(3-fluoropropyl)- N-[3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5- a]pyrimidin-7-yl]-phenyl]-acetamide ( 5b) showed an IC 50 value of 2.78 ± 0.63 nM comparable to the lead compound Indiplon (IC 50 3.29 ± 0.37 nM), thus making it an interesting candidate for further investigations. In addition to the fluorinated reference compounds, suitable precursors for 18F-radiolabelling studies have been synthesized.

Fe(II)-Induced Reduction of Labelled Endoperoxides. NMR Degradation Studies on G3 Factor and Its Methyl Ether

The behavior of G3 factor and of its methylated or fluorinated analogues G3Me and G3F, was studied under Fe(II) conditions. Degradation products were isolated and characterized in each case. The use of labelled compounds allowed us to propose mechanisms in which a tertiary radical is involved. This radical rearranges by 5-exo-trig cyclization, or disproportionates in the case of G3Me. A correlation between antiplasmodial activity and stability of this radical is proposed.

Anaerobic Reductive Dechlorination of 1-Chloro-1-fluoroethene To Track the Transformation of Vinyl Chloride

1-Chloro-1-fluoroethene (1,1-CFE) was studied as a reactive tracer to quantify the anaerobic transformation of vinyl chloride (VC). Batch kinetic studies of 1,1-CFE and VC transformation were performed with an enrichment culture obtained from the Evanite site in Corvallis, OR. The culture is capable of completely transforming trichloroethene (TCE) through cis-dichloroethene (c-DCE) and VC to ethene. The culture also transforms fluorinated analogues, such as trichlorofluoroethene (TCFE), to fluoroethene (FE) as a final product. The transformation sequence of the fluorinated analogue was correlated with that achieved for the chlorinated ethene with the same degree of chloride substitution. For example, the production of 1,1-CFE, the major CFE isomer formed from TCFE transformation, was correlated with the production of VC from TCE transformation. Since the 1,1-CFE and its product, FE, have a distinct analytical signature, 1,1-CFE may be used as a reactive in situ tracer to evaluate the VC transformation potential. The half-saturated constants (K(S)) of VC and 1,1-CFE were 63 and 87 microM, respectively, while similar maximum utilization rates (kmaxX) of 334 and 350 microM/d were achieved. Acetylene inhibited both VC and 1,1-CFE transformation. A competitive inhibition model with the independently measured K(S) values used as the inhibition constants predicted rates of transformation of both VC and 1,1-CFE when both compounds were present. 1,1-CFE transformation was also tested with three different cultures. With all the cultures, 1,1-CFE transformation was associated with VC transformation to ethene, and the rates of transformation were comparable. The results demonstrated that 1,1-CFE was a good reactive surrogate for evaluating the rates of VC transformation.

Tertiary arsine oxides: active and selective catalysts for epoxidation with hydrogen peroxide

Abstract Tertiary arsines are active and selective catalysts for the epoxidation of a variety of alkenes with hydrogen peroxide at low catalyst loading (1–5 mol%); highly fluorinated analogues of these arsines can be recovered and reused with moderate efficiency.

Synthetic studies of fluorinated analogues of 1-azafagomine: Remarkable nucleophilic substitution of fluorine by hydrazine

(±)-5-fluoro-4-hydroxy-3-hydroxymethylhexahydropyridazine ( 7 ) and some other azafagomine analogues were synthesis ed with the aim of comparing their glycosidase inhibition to that of (±)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine (1-azafagomine). Both in the synthesis of 7 and in the attempted synthesis of 4,5-dihydroxy-3-fluoromethylhexahydropyridazine, a remarkable degree of nucleophilic substitution of fluorine by hydrazine was observed in the final deprotection step involving hydrazinolysis. Fluorine analogue 7 was a considerably weaker glycosidase inhibitor than 1 , suggesting that the 3-OH of 1 play a role in its binding by acting as a hydrogen bond donator. Both secondary and primary alkyl fluoride was found to be substituted, in some cases quantitatively, with hydrazine.