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.
Structural and Computational Analysis of 2-Halogeno-Glycosyl Cations in the Presence of a Superacid: An Expansive Platform
Lebedel, Ludivine,Ardá, Ana,Martin, Amélie,Désiré, Jér?me,Mingot, Agnès,Aufiero, Marialuisa,Aiguabella Font, Nuria,Gilmour, Ryan,Jiménez-Barbero, Jesus,Blériot, Yves,Thibaudeau, Sébastien
supporting information, p. 13758 - 13762 (2019/08/21)
An expansive NMR-based structural analysis of elusive glycosyl cations derived from natural and non-natural monosaccharides in superacids is disclosed. For the first time, it has been possible to explore the consequence of deoxygenation and halogen substitution at the C2 position in a series of 2-halogenoglucosyl, galactosyl, and mannosyl donors in the condensed phase. These cationic intermediates were characterized using low-temperature in situ NMR experiments supported by DFT calculations. The 2-bromo derivatives display intramolecular stabilization of the glycosyl cations. Introducing a strongly electron-withdrawing fluorine atom at C2 exerts considerable influence on the oxocarbenium ion reactivity. In a superacid, these oxocarbenium ions are quenched by weakly coordinating SbF6? anions, thereby demonstrating their highly electrophilic character and their propensity to interact with poor nucleophiles.
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.
