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Ligand-based

Fragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous screening techniques, fluorine-detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high-quality and diverse library containing nearly 4000 fragments and screening for target-specific binders within days. At the core of the approach is a novel broadband relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like 19 F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets.

Fragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous screening techniques, fluorine-detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high-quality and diverse library containing nearly 4000 fragments and screening for target-specific binders within days. At the core of the approach is a novel broadband relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like

The objective of our study was to evaluate the impact of body mass index (BMI) on dose, diagnostic performance, and image quality of a low-dose CT examination for renal colic.This retrospective study included all patients who underwent a low-dose CT examination for renal colic performed during the year 2012 with automatic tube current modulation, adaptive statistical iterative reconstruction, and a low tube voltage (kV). Three readers independently reviewed all images for the presence of renal colic and evaluated diagnostic confidence and image quality. The results and doses were compared among patients grouped by body mass index (BMI) and between patients with a BMI25 and those with a BMI≥25.Eighty-six patients were included in the study: 39 patients had a BMI25 and 47 had a BMI≥25. No statistically significant difference was found between the accuracy rates for the diagnosis of renal colic when the rates of the three independent readers were averaged for both BMI groups (95.7% vs 96.4%, respectively; p=0.83). Image quality and diagnostic confidence scores were significantly better for patients with a BMI≥25 than for patients with a BMI25 (mean image quality score, 3.7 vs 3.4, p0.001; mean diagnostic confidence score, 2.8 vs 2.5, p0.001). The mean radiation dose for patients with a BMI25 was 2.4 mGy compared with 3.7 mGy for patients with a BMI≥25 (p0.001).The diagnostic performance of our low-dose CT protocol for renal colic was excellent for all patients, and image quality and diagnostic confidence were significantly better for patients with a BMI≥25. However, our protocol also required exposure to a greater dose of radiation for these overweight and obese patients.

Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases.

A thin conducting film of an organic composite material made of n-butylcellulose and polythiophene has been fabricated. Thin oriented films of n-butylcinnamoylcellulose were deposited on a conducting substrate by the Langmuir−Blodgett technique and stabilized by cross-linking through UV irradiation. Subsequent exposure to a solution of 3-pentylthiophene followed by electropolymerization led to the formation of polypentylthiophene (PPT) within the alkylcellulose matrix. The structure of the composite material has been characterized by various spectroscopies, microscopies, and microanalysis techniques. The composite material is made of domains of PPT oriented along the cellulose backbones. In the case of large domains (up to 35 × 150 μm2) there is a segregation between cellulose and PPT. However, for small domains (a few square microns), the two polymers seem to be intimately mixed and PPT is oriented at the molecular level. In all cases, the alkylcellulose stabilizes the PPT film in organic solvents and do...

Two anomeric analogues of glucose labelled with 123 iodine in position 6, proposed as tracers of glucose transport in vivo , have been synthesized: α- and β-methyl-6-deoxy-6-iodo-d-glucopyranoside (αMDIG and βMDIG). The aim of this study was to determine whether these molecules interact with the glucose transporter and whether they could be used as tracers of glucose transport in vivo . The biodistribution of αMDIG and βMDIG was studied in the mouse in vivo . To determine if these two anomers enter the cell via the glucose transporter, their uptake was measured in isolated perfused rat hearts, in human erythrocytes in suspension, and in cardiomyocytes of neonatal rat in culture. Both αMDIG and βMDIG had similar repartitions in the mouse: myocardial uptake averaged 7% of the injected dose/g of organ at 2 min postinjection and αMDIG competed with d-glucose to enter the cells. Insulin produced a 123% increase of its uptake in isolated perfused rat hearts and a 100% increase in cardiomyocytes of neonatal rat in culture. αMDIG uptake was lowered in the presence of glucose transport inhibitors in each experimental model. An interaction between βMDIG and glucose transporters was observed only in human erythrocytes in suspension. Only αMDIG interacts with the glucose transporter, and thus could be used to estimate glucose transport in vivo .

Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance.

The identification of compounds that bind to a protein of interest is of central importance in contemporary drug research. For screening of compound libraries, NMR techniques are widely used, in particular the Water-Ligand Observed via Gradient SpectroscopY (WaterLOGSY) experiment. Here we present an optimized experiment, the polarization optimized WaterLOGSY (PO-WaterLOGSY). Based on a water flip-back strategy in conjunction with model calculations and numerical simulations, the PO-WaterLOGSY is optimized for water polarization recovery. Compared to a standard setup with the conventional WaterLOGSY, time consuming relaxation delays have been considerably shortened and can even be omitted through this approach. Furthermore, the robustness of the pulse sequence in an industrial setup was increased by the use of hard pulse trains for selective water excitation and water suppression. The PO-WaterLOGSY thus yields increased time efficiency by factor of 3-5 when compared with previously published schemes. These time savings have a substantial impact in drug discovery, since significantly larger compound libraries can be tested in screening campaigns.

International audience; Several new phthalocyanine-polysiloxanes containing pyridine moieties with potential use for organizing electroactive monomers have been synthesized. The compounds are slightly soluble in organic solvents due to their polycationic nature. However, when soluble enough, these oligomers give Langmuir-Blodgett films macroscopically in-plane oriented in which the long axis of the rod-like molecules lies parallel to the dipping direction.

The synthesis and characterization of Cell-SAc 3, a cellulose isopentyl (IP) ether with additional pendant S-acetyl (SAc) moieties (degree of substitution DS IP = 2.5, DS SAc = 0.4) are reported. Cell-SAc forms stable monolayers at the air-water interface once spread from dilute chloroform solution. The pressure-area isotherm of Cell-SAc is nearly identical to the parent Cell-IP 1, both exhibiting an expanded liquid phase at surface areas of 70 and 67 A, respectively. The similarity of the two isotherms shows that the presence of the S-acetyl substituent does not result in an increase in the molecular area, at which the liquid-crystal analogous phase occurs. This observation suggests that the side-chains with the pendant S-acetyl goup are oriented away from the water surface. Monolayers of Cell-SAc can be efficiently transferred onto silicon and hydrophobized glass or quartz substrates by a downstroke and upstroke technique. Resulting multilayers were characterized using X-ray reflection. FTIR, and UV-vis spectroscopy. The presence of S-acetyl moieties was found to increase the monolayer thickness relative to the parent Cell-IP. The cleavage of the S-acetyl group within thc LB film is reported.

A glucose analogue labelled with iodine-123 in position 6 has been synthesized: [123I]-6-deoxy-6-iodo- d -glucose (6DIG). The aim of this study was to examine its biological behaviour in order to assess whether it could be used to evaluate glucose transport with SPECT. To establish whether 6DIG enters the cells using the glucose transporter, four biological models have been used: human erythrocytes in suspension, neonatal rat cardiomyocytes in culture, isolated perfused rat hearts, and biodistribution in mice. 6DIG competed with d -glucose to enter the cells and its entry was increased by insulin and inhibited in the presence of cytochalasin B. The biological behaviour of 6DIG was similar to that of 3-O-methyl- d -glucose. 6DIG is a tracer of glucose transport which is very promising for clinical studies.

6-deoxy-6-iodo-D-glucose (6-DIG) was rapidly taken up by adipocytes. Insulin increased 6-DIG transport in adipocytes isolated from both rats and mice. This stimulation was more important in rat than in mouse adipocytes, in agreement with their respective amount of Glut 4 transporters. In two insulin resistant states, the biological behavior of 6-DIG and 3-O-methyl-D-glucose was similar. These results indicated that 6-DIG, which was transported into the cells via the glucose transporters, could be potentially useful to measure modifications of glucose transport.

For an iodinated analogue of glucose to be useful for evaluating glucose uptake using single-photon emission computed tomography (SPECT), it must enter the cell via the same transporter as glucose and accumulate within the cell without being degraded. The biological behavior of the iodinated tracer must therefore be similar to that of 2-deoxy-d-[1- 14 C]-glucose (2-DG). In the present study, four experimental models (biodistribution in mouse, isolated rat heart, human erythrocytes in suspension and cultured neonatal rat cardiomyocytes) have been chosen and protocols have been set up which allow for the examination of small quantities of iodinated analogues of glucose. The uptakes of 2-DG and of l-[1- 14 C]-glucose have been measured in these models to establish reference values which will be compared with uptake values for iodinated analogues of glucose.