Conformational Analysis of 1,3-Difluorinated Alkanes.

Fluorine substitution can have a profound impact on molecular conformation. Here, we present a detailed conformational analysis of how the 1,3-difluoropropylene motif (-CHF-CH2-CHF-) determines the conformational profiles of 1,3-difluoropropane, anti- and syn-2,4-difluoropentane, and anti- and syn-3,5-difluoroheptane. It is shown that the 1,3-difluoropropylene motif strongly influences alkane chain conformation, with a significant dependence on the polarity of the medium. The conformational effect of 1,3-fluorination is magnified upon chain extension, which contrasts with vicinal difluorination. Experimental evidence was obtained from NMR analysis, where polynomial complexity scaling simulation algorithms were necessary to enable J-coupling extraction from the strong second-order spectra, particularly for the large 16-spin systems of the difluorinated heptanes. These results improve our understanding of the conformational control toolkit for aliphatic chains, yield simple rules for conformation population analysis, and demonstrate quantum mechanical time-domain NMR simulations for liquid state systems with large numbers of strongly coupled spins.

Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

Obtaining Pure 1H NMR Spectra of Individual Pyranose and Furanose Anomers of Reducing Deoxyfluorinated Sugars.

Due to tautomeric equilibria, NMR spectra of reducing sugars can be complex with many overlapping resonances. This hampers coupling constant determination, which is required for conformational analysis and configurational assignment of substituents. Given that mixtures of interconverting species are physically inseparable, easy-to-use techniques that enable facile full 1H NMR characterization of sugars are of interest. Here, we show that individual spectra of both pyranoside and furanoside forms of reducing fluorosugars can be obtained using 1D FESTA. We discuss the unique opportunities offered by FESTA over standard sel-TOCSY and show how it allows a more complete characterization. We illustrate the power of FESTA by presenting the first full NMR characterization of many fluorosugars, including of the important fluorosugar 2-deoxy-2-fluoroglucose. We discuss in detail all practical considerations for setting up FESTA experiments for fluorosugars, which can be extended to any mixture of fluorine-containing species interconverting slowly on the NMR frequency-time scale.

Synthesis and Structural Characteristics of all Mono- and Difluorinated 4,6-Dideoxy-d-xylo-hexopyranoses.

Protein-carbohydrate interactions are implicated in many biochemical/biological processes that are fundamental to life and to human health. Fluorinated carbohydrate analogues play an important role in the study of these interactions and find application as probes in chemical biology and as drugs/diagnostics in medicine. The availability and/or efficient synthesis of a wide variety of fluorinated carbohydrates is thus of great interest. Here, we report a detailed study on the synthesis of monosaccharides in which the hydroxy groups at their 4- and 6-positions are replaced by all possible mono- and difluorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative substituents, either as protecting groups or as deoxygenation intermediates, was generally beneficial for increasing deoxyfluorination yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/fluorination at the 4,6-positions caused very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/ß anomeric ratios were identified. Increasing fluorine content always increased the α/ß ratio, with very little difference between regio- or stereoisomers, except when 4,6-difluorinated.

Synthesis and Properties of Open Fullerenes Encapsulating Ammonia and Methane.

We describe the synthesis and characterisation of open fullerene (1) and its reduced form (2) in which CH4 and NH3 are encapsulated, respectively. The 1 H NMR resonance of endohedral NH3 is broadened by scalar coupling to the quadrupolar 14 N nucleus, which relaxes rapidly. This broadening is absent for small satellite peaks, which are attributed to natural abundance 15 N. The influence of the scalar relaxation mechanism on the linewidth of the 1 H ammonia resonance is probed by variable temperature NMR. A rotational correlation time of τc =1.5 ps. is determined for endohedral NH3 , and of τc =57±5 ps. for the open fullerene, indicating free rotation of the encapsulated molecule. IR spectroscopy of NH3 @2 at 5 K identifies three vibrations of NH3 (ν1 , ν3 and ν4 ) redshifted in comparison with free NH3 , and temperature dependence of the IR peak intensity indicates the presence of a large number of excited translational/ rotational states. Variable temperature 1 H NMR spectra indicate that endohedral CH4 is also able to rotate freely at 223 K, on the NMR timescale. Inelastic neutron scattering (INS) spectra of CH4 @1 show both rotational and translational modes of CH4 . Energy of the first excited rotational state (J=1) of CH4 @1 is significantly lower than that of free CH4 .

A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives.

Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH···O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine.

Biasing hydrogen bond donating host systems towards chemical warfare agent recognition.

A series of neutral ditopic and negatively charged, monotopic host molecules have been evaluated for their ability to bind chloride and dihydrogen phosphate anions, and neutral organophosphorus species dimethyl methylphosphonate (DMMP), pinacolyl methylphosphonate (PMP) and the chemical warfare agent (CWA) pinacolyl methylphosphonofluoridate (GD, soman) in organic solvent via hydrogen bonding. Urea, thiourea and boronic acid groups are shown to bind anions and neutral guests through the formation of hydrogen bonds, with the urea and thiourea groups typically exhibiting higher affinity interactions. The introduction of a negative charge on the host structure is shown to decrease anion affinity, whilst still allowing for high stability host-GD complex formation. Importantly, the affinity of the host for the neutral CWA GD is greater than for anionic guests, thus demonstrating the potential for selectivity reversal based on charge repulsion.

Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method.

Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non-UV-active compounds. A new variation of the shake-flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported.

Dynamic covalent transport of amino acids across lipid bilayers.

We report a dynamic covalent approach to transmembrane transport of amino acids by the formation of a three-component assembly. A mixture of a squaramide and a lipophilic and electrophilic aldehyde is shown to synergistically transport highly polar glycine (Gly) across vesicle membranes. The transport was investigated by a (13)C NMR assay, an osmotic response assay, a newly developed fluorescence assay suitable for measuring Gly influx, and other fluorescence assays for leakage and pH change. The transport is proposed to occur via a hydrogen-bonded anionic glycine hemiaminal/imine, accompanied by transport of OH(-) in the opposite direction. Several control experiments support the role of hemiaminal/imine in the observed facilitated Gly transport. Proton NMR studies of a biphasic system show the presence of both the hemiaminal and imine formed between Gly and an aldehyde. Interestingly, the synergistic effect has also been observed for sarcosine, which can form hemiaminals but not imines. The results demonstrate the potential of hemiaminal formation for the facilitated transport of substrates containing primary and secondary amino groups.

Intramolecular OH⋠⋠⋠Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif.

Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time-and in contrast to earlier reports-the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding (h1) JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9 Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the "rule of shielding" applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.

Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding.

Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone.

A Resin-linker-vector approach to radiopharmaceuticals containing 18F: application in the synthesis of O-(2-[18F]-fluoroethyl)-L-tyrosine.

A Resin-linker-vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide (18)F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene-bound arylsulfonate linker with [(18)F]-fluoride ion. Three model linker-vector molecules 7a-c containing different alkyl spacer groups were assembled in solution from (4-chlorosulfonylphenyl)alkanoate esters, exploiting a lipase-catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker-vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8a-c with acetate, butyrate and hexanoate spacers, which were characterised by using magic-angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8a,b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4-fluorobutyl)phenylcarbamic acid tert-butyl ester (9) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60%) of the (18) F-labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O-(2-[(18)F]-fluoroethyl)-L-tyrosine ([(18) F]-FET), delivering protected [(18) F]-FET in >90% RCY. Acid deprotection gave [(18)F]-FET in an overall RCY of 41% from the RLV.

Benzimidazole-based anion receptors exhibiting selectivity for lactate over pyruvate.

The influence of anions on tautomerism in benzimidazole containing anion receptors has been studied via a variety of techniques in both solution and the solid state. The results show that hydrogen bonding interactions between the receptors and guests have a significant effect of the nature of the tautomer present. The compounds show a preference for complexation of lactate over pyruvate.

Benzimidazole-based anion receptors: tautomeric switching and selectivity.

Tautomeric switching is observed in a series of benzimidazole-based anion receptors upon addition of basic anions. An N-methylbenzimidazole based receptor selectively interacts with dihydrogen phosphate over a variety of other putative anionic guests via a combination of donated and accepted hydrogen bonds.

Hand It to Dr Google: The Quality of Online Information on Ganglion Cysts.

Background: The internet is becoming a common source of health information for hand surgery patients. This study evaluates the quality of web-based resources on ganglion cysts of the hand. Methods: We completed a search for "ganglion cyst" on 3 search engines (Google, Dogpile, and Yippy). The quality of the top-100 patient education websites was assessed using a validated internet rating tool. Websites were evaluated based on affiliation, accountability, currency, interactivity, website organization, readability, coverage, and accuracy. Results: Of the 100 websites, the majority (74%) had commercial affiliations. Only 34% of websites identified an author, and even fewer identified the authors' credentials (27%) or affiliations (26%). A third of the websites cited references, and less than half provided an update date. The average readability based on Flesch-Kincaid grade level was 9.2, and only 3% could be read at or below 6th grade reading level. Prevention was the most poorly covered topic at 13% due to omission. In all, 66% of the websites were completely accurate in terms of global accuracy. Websites were most likely to present inaccurate information on treatment, often failing to mention conservative treatment (watch-and-wait approach) or promoting the use of natural health products. We also found 5% of websites presented closed rupture of the ganglion cyst as a legitimate home remedy. Conclusions: The overall quality of online information on ganglion cysts is highly variable and may occasionally be harmful for patients. It is increasingly important for physicians to prompt patients about their internet use.

Biophysical Survey of Small-Molecule ß-Catenin Inhibitors: A Cautionary Tale.

The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases. ß-Catenin is a multifunctional protein within this pathway and an attractive yet challenging therapeutic target, most notably in oncology. This has stimulated the search for potent small-molecule inhibitors binding directly to the ß-catenin surface to inhibit its protein-protein interactions and downstream signaling. Here, we provide an account of the claimed (and some putative) small-molecule ligands of ß-catenin from the literature. Through in silico analysis, we show that most of these molecules contain promiscuous chemical substructures notorious for interfering with screening assays. Finally, and in line with this analysis, we demonstrate using orthogonal biophysical techniques that none of the examined small molecules bind at the surface of ß-catenin. While shedding doubts on their reported mode of action, this study also reaffirms ß-catenin as a prominent target in drug discovery.

Similar meltwater contributions to glacial sea level changes from Antarctic and northern ice sheets.

The period between 75,000 and 20,000 years ago was characterized by high variability in climate and sea level. Southern Ocean records of ice-rafted debris suggest a significant contribution to the sea level changes from melt water of Antarctic origin, in addition to likely contributions from northern ice sheets, but the relative volumes of melt water from northern and southern sources have yet to be established. Here we simulate the first-order impact of a range of relative meltwater releases from the two polar regions on the distribution of marine oxygen isotopes, using an intermediate complexity model. By comparing our simulations with oxygen isotope data from sediment cores, we infer that the contributions from Antarctica and the northern ice sheets to the documented sea level rises between 65,000 and 35,000 years ago were approximately equal, each accounting for a rise of about 15 m. The reductions in Antarctic ice volume implied by our analysis are comparable to that inferred previously for the Antarctic contribution to meltwater pulse 1A (refs 16, 17), which occurred about 14,200 years ago, during the last deglaciation.

Blinded, prospective, randomized clinical trial comparing volar, dorsal, and custom thermoplastic splinting in treatment of acute mallet finger.

PURPOSE: To compare volar, dorsal, and custom splinting techniques in acute Doyle I mallet finger injuries. METHODS: We developed a radiographic lag measurement using the contralateral normal digit as an internal control for establishing the approximate preinjury maximal extension of the mallet finger. The difference in maximal distal interphalangeal joint extension between the injured and contralateral normal digit was defined as the radiographic lag difference. We randomized 87 subjects meeting the inclusion criteria to one of 3 splint types: volar padded aluminum splint, dorsal padded aluminum splint, and custom thermoplastic. Splints were continued for 6 weeks full-time. A total of 77 subjects were available for measurement of the primary outcome measure: radiographic lag difference at week 12. Secondary outcome measures were recorded at weeks 7 and 24. RESULTS: No lag difference was demonstrated at week 12 (p = .12), although a trend suggesting superiority (closest value to 0 difference) of the custom thermoplastic splint was observed. The mean radiographic lag differences were -16.2 degrees (95% confidence interval [CI], -21.3 degrees to -11.0 degrees ) for the dorsal padded aluminum splint, -13.6 degrees (95% CI, -18.0 degrees to -9.2 degrees ) for the volar padded aluminum splint, and -9.0 degrees (95% CI, -14.5 degrees to 3.4 degrees ) for the custom thermoplastic splint. Secondary between-group analyses showed no differences for radiographic or clinical lag, Michigan Hand Outcome Questionnaire scores, or complications. Secondary analyses of the whole cohort suggested that clinical measurement overestimates true lag, increased lag occurs after discontinuation of splinting, and clinically measured improvement in lag is noted at week 24. CONCLUSIONS: No lag difference was demonstrated between custom thermoplastic, dorsal padded aluminum splint, and volar padded aluminum splinting for Doyle I acute mallet fingers. Clinical measurement overestimates true lag in mallet injuries. Increased lag occurs after discontinuation of splinting. Increased age and complications correlate with worse radiographic lag.

A New Straightforward Method for Lipophilicity (logP) Measurement using 19F NMR Spectroscopy.

Fluorination has become an effective tool to optimize physicochemical properties of bioactive compounds. One of the applications of fluorine introduction is to modulate the lipophilicity of the compound. In our group, we are interested in the study of the impact of fluorination on lipophilicity of aliphatic fluorohydrins and fluorinated carbohydrates. These are not UV-active, resulting in a challenging lipophilicity determination. Here, we present a straightforward method for the measurement of lipophilicity of fluorinated compounds by 19F NMR spectroscopy. This method requires no UV-activity. Accurate solute mass, solvent and aliquot volume are also not required to be measured. Using this method, we measured the lipophilicities of a large number of fluorinated alkanols and carbohydrates.

Tissue Expansion for Severe Foot and Ankle Deformities: A 16-Year Review.

BACKGROUND: Tissue expansion in the lower extremity is controversial, with studies reporting complication rates as high as 83%. Few studies have looked at tissue expansion prior to orthopaedic correction of severe foot and ankle deformities, and those available are restricted to clubfoot in the pediatric population. Here, we report the largest case series on the use of tissue expanders for the reconstruction of severe foot and ankle deformity and the only report in adults. METHODS: This is a retrospective chart review of the senior author's practice over a 16-year study period. All patients over 18 years of age who underwent tissue expansion prior to definitive orthopaedic correction of a severe foot and ankle deformity were included. Patient demographics, etiology of deformity, rate of expansion, and complications were recorded. Major complications were defined as those which required surgical intervention. Data were analyzed using descriptive statistics. RESULTS: Nineteen cases were performed on 16 patients. Our overall complication rate was 31.6% (6/19), with major complications occurring in 21.1% (4/19) of cases, and minor complications occurring in 10.5% (2/19) of cases. Despite this, 94.7% (18/19) of cases went on to receive definitive orthopaedic correction after tissue expansion. No demographic parameters were associated with occurrence of complications. CONCLUSIONS: This represents the largest report on lower extremity tissue expansion for severe foot and ankle deformity correction. While we observed complications in 31.6% of patients, 94.7% of cases went on to receive definitive orthopaedic correction with successful primary closure.

HISTORIQUE: L'expansion tissulaire des membres inférieurs est controversée, car des études font état d'un taux de complications atteignant les 83 %. Peu d'études ont porté sur l'expansion tissulaire avant la correction orthopédique de graves déformations du pied et de la cheville, et celles qui existent se limitent au pied bot dans la population pédiatrique. Les auteurs rendent compte de la plus grande série de cas sur l'utilisation d'expandeurs tissulaires en vue de la reconstruction de graves déformations du pied et de la cheville, la seule à être menée chez des adultes. MÉTHODOLOGIE: La présente étude rétrospective traite des dossiers de l'auteur principal sur une période de 16 ans. Tous les patients de plus de 18 ans qui ont subi une expansion tissulaire avant la correction orthopédique définitive d'une grave déformation du pied et de la cheville en ont fait partie. Les chercheurs ont consigné la démographie des patients, l'étiologie des déformations, le taux d'expansion et les complications. Ils ont défini les complications majeures comme celles qui exigent une intervention chirurgicale. Ils ont analysé les données à l'aide de statistiques descriptives. RÉSULTATS: Les chercheurs ont relevé 19 cas chez 16 patients. Le taux de complications global s'élevait à 31,6 % (six cas sur 19). Des complications majeures se sont produites dans 21,1 % des cas (quatre sur 19) et des complications, mineures, dans 10,5 % des cas (deux sur 19). Malgré tout, 94,7 % des cas (18 sur 19) ont subi une correction orthopédique définitive après l'expansion tissulaire. Aucun paramètre démographique ne laissait présager les complications. CONCLUSIONS: La présente étude est le rapport le plus vaste des expansions tissulaires pour corriger de graves déformations du pied et de la cheville. Les auteurs ont observé des complications chez 31,6 % des patients, mais 94,7 % des cas ont profité d'une correction orthopédique définitive et d'une fermeture primaire réussie.