Synthesis of difluoromethylphosphonamidates by direct addition of amine

The one step synthesis of difluoromethylphosphonamidates from dialkylphosphonates is reported. The addition of lithiated amides onto dialkyl difluoromethylphosphonates afforded the corresponding phosphonamidates, as potential prodrug precursors. The remarkable high stability of these phosphonamidates in acidic medium was studied by ³¹P NMR.     

A new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution.     

First insights into the protonation of dissymetrically disubstituted di-iron azadithiolate models of the [FeFe]H2ases active site

Dissymetrically disubstituted di-iron azadithiolate complexes [Fe2(CO)4(kappa 2-LL){mu-SCH2N(iPr)CH2S}] (LL = dppe, phen) protonate exclusively at the N atom of the bridge, like the hexacarbonyl precursor but in contrast to symmetrically disubstituted analogues; substitution of dppe for two CO groups noticeably increases the kinetics of the electrocatalytic proton reduction process.     

Water-soluble red-emitting distyryl-borondipyrromethene (BODIPY) dyes for biolabeling

A series of water-soluble red-emitting distyryl-borondipyrromethene (BODIPY) dyes were designed and synthesized by using three complementary approaches aimed at introducing water-solubilizing groups on opposite faces of the fluorescent core to reduce or completely suppress self-aggregation. An additional carboxylic acid functional group was introduced at the pseudo-meso position of the BODIPY scaffold for conjugation to amine-containing biomolecules/biopolymers. The optical properties of these dyes were evaluated under simulated physiological conditions (i.e., phosphate-buffered saline (PBS), pH 7.5) or in pure water. The emission wavelength (λ(max)) of these labels was found in the 640-660 nm range with quantum yields from modest to unprecedentedly high values (4 to 38%). The bioconjugation of these distyryl-BODIPY dyes with bovine serum albumin (BSA) and the monoclonal antibody (mAb) 12A5 was successfully performed under mild aqueous conditions.     

Improved synthetic pathway for the derivatization of huprine scaffold

In the search of new huprine-like acetylcholinesterase binders, we have developed an improved, shorter, and high-scalable synthetic pathway for the huprine synthesis based on a Reformatsky reaction-one-pot fragmentation/Friedländer condensation sequence. An extension for the one-pot synthesis of huprine-like 4-chloroquinolines is also presented. This modified route is particularly interesting as it allows to yield a huprine containing a functional group at position 9 in only three steps from commercially available material.     

Time reversed elastic nonlinearity diagnostic applied to mock osseointegration monitoring applying two experimental models

This study broadens vibration-like techniques developed for osseointegration monitoring to the nonlinear field. The time reversed elastic nonlinearity diagnostic is applied to two mock models. The first one consists of tightening a dental implant at different torques in a mock cortical bone; the second one allows one to follow glue curing at the interface between a dental implant and a mock jaw. Energy is focused near the implant interface using the time reversal technique. Two nonlinear procedures termed pulse inversion and the scaling subtraction method, already used successfully in other fields such as contrast agents and material characterization, are employed. These two procedures are compared for both models. The results suggest that nonlinear elasticity can provide new information regarding the interface, complementary to the linear wave velocity and attenuation. The curing experiment exhibits an overall low nonlinear level due to the fact that the glue significantly damps elastic nonlinearity at the interface. In contrast, the torque experiment shows strong nonlinearities at the focus time. Consequently, a parallel analysis of these models, both only partially reflecting a real case, enables one to envisage future in vivo experiments.     

A New Alternative Tool to Analyse Glycosylation in Monoclonal Antibodies Based on Drop-Coating Deposition Raman imaging: A Proof of Concept

Glycosylation is considered a critical quality attribute of therapeutic proteins as it affects their stability, bioactivity, and safety. Hence, the development of analytical methods able to characterize the composition and structure of glycoproteins is crucial. Existing methods are time consuming, expensive, and require significant sample preparation, which can alter the robustness of the analyses. In this context, we developed a fast, direct, and simple drop-coating deposition Raman imaging (DCDR) method combined with multivariate curve resolution alternating least square (MCR-ALS) to analyze glycosylation in monoclonal antibodies (mAbs). A database of hyperspectral Raman imaging data of glycoproteins was built, and the glycoproteins were characterized by LC-FLR-MS as a reference method to determine the composition in glycans and monosaccharides. The DCDR method was used and allowed the separation of excipient and protein by forming a “coffee ring”. MCR-ALS analysis was performed to visualize the distribution of the compounds in the drop and to extract the pure spectral components. Further, the strategy of SVD-truncation was used to select the number of components to resolve by MCR-ALS. Raman spectra were processed by support vector regression (SVR). SVR models showed good predictive performance in terms of RMSECV, R²_CV.