141395-48-4Relevant articles and documents
Polyfluoroglycoside Synthesis via Simple Alkylation of an Anomeric Hydroxyl Group: Access to Fluoroetoposide Analogues
Tremblay, Thomas,St-Gelais, Jacob,Houde, Maxime,Giguere, Denis
, p. 4812 - 4824 (2021/04/02)
In this work, we have developed a new approach for the synthesis of fluoroglycoside analogues. This strategy used a simple alkylation protocol and allowed the installation of a simple aglyconic alkane with the β configuration. Moreover, the glycosylation of fluorinated glucoside analogues with 4′-demethylepipodophyllotoxin furnished novel fluoroetoposide analogues. In these cases, the α anomers were formed as major products with an S configuration at the C-4 of the aglycone.
Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions
Denavit, Vincent,Lainé, Danny,Bouzriba, Chahrazed,Shanina, Elena,Gillon, émilie,Fortin, Sébastien,Rademacher, Christoph,Imberty, Anne,Giguère, Denis
supporting information, p. 4478 - 4490 (2019/03/07)
The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of “drug-like” low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.
KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists
Zihlmann, Pascal,Silbermann, Marleen,Sharpe, Timothy,Jiang, Xiaohua,Mühlethaler, Tobias,Jakob, Roman P.,Rabbani, Said,Sager, Christoph P.,Frei, Priska,Pang, Lijuan,Maier, Timm,Ernst, Beat
, p. 13049 - 13057 (2018/08/17)
Affinity data, such as dissociation constants (KD) or inhibitory concentrations (IC50), are widely used in drug discovery. However, these parameters describe an equilibrium state, which is often not established in vivo due to pharmacokinetic effects and they are therefore not necessarily sufficient for evaluating drug efficacy. More accurate indicators for pharmacological activity are the kinetics of binding processes, as they shed light on the rate of formation of protein–ligand complexes and their half-life. Nonetheless, although highly desirable for medicinal chemistry programs, studies on structure–kinetic relationships (SKR) are still rare. With the recently introduced analytical tool kinITC this situation may change, since not only thermodynamic but also kinetic information of the binding process can be deduced from isothermal titration calorimetry (ITC) experiments. Using kinITC, ITC data of 29 mannosides binding to the bacterial adhesin FimH were re-analyzed to make their binding kinetics accessible. To validate these kinetic data, surface plasmon resonance (SPR) experiments were conducted. The kinetic analysis by kinITC revealed that the nanomolar affinities of the FimH antagonists arise from both (i) an optimized interaction between protein and ligand in the bound state (reduced off-rate constant koff) and (ii) a stabilization of the transition state or a destabilization of the unbound state (increased on-rate constant kon). Based on congeneric ligand modifications and structural input from co-crystal structures, a strong relationship between the formed hydrogen-bond network and koff could be concluded, whereas electrostatic interactions and conformational restrictions upon binding were found to have mainly an impact on kon.
