Alkali-metal-catalyzed synthesis of isoureas from alcohols and carbodiimides

International audienceCurrent synthetic methods for the formation of isoureas rely on the addition of the alcohol (R'OH) to the corresponding carbodiimide (RN=C=NR). State-of-the-art catalysts rely on transition metal and actinide complexes. Copper (CuCl, CuCl$_2$, Cu$_2$O) and zinc (ZnCl$_2$) salts are reported to act as Lewis acids , able to enhance the electrophilicity of the carbodiimide reagent. Recently, in 2016, Eisen described new actinide complexes (U[N(SiMe$_3$)$_2$]$_3$ and [(Me$_3$Si)$_2$N]2An[κ$^2$ (N,C)-CH$_2$Si(CH$_3$)$_2$N(SiMe$_3$)] (An = Th or U)) able to catalyze the formation of isoureas under mild conditions. Capitalizing on our knowledge on the chemical reactivity of guanidine bases and alkali metal like Lewis acid, we have recently designed the first alkali metal catalysts able to facilitate the addition of alcohols to carbodiimides. The role and influence of the alkali metal has been investigated by controlling the Lewis acidity of the alkali metal with exogenous ligands. Experimental studies, combined with DFT calculations, offer a new vision on the active role of alkali metal cations in catalysis

Prions activate a p38 MAPK synaptotoxic signaling pathway.

Synaptic degeneration is one of the earliest pathological correlates of prion disease, and it is a major determinant of the progression of clinical symptoms. However, the cellular and molecular mechanisms underlying prion synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment of cultured hippocampal neurons with purified PrPSc, the infectious form of the prion protein, induces rapid retraction of dendritic spines, an effect that is entirely dependent on expression of endogenous PrPC by the target neurons. Here, we use this system to dissect pharmacologically the underlying cellular and molecular mechanisms. We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines. Synaptic degeneration is restricted to excitatory synapses, spares presynaptic structures, and results in decrements in functional synaptic transmission. Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration. Moreover, p38 MAPK inhibitors actually reverse the degenerative process after it has already begun. We also show that, while PrPC mediates the synaptotoxic effects of both PrPSc and the Alzheimer's Aβ peptide in this system, the two species activate distinct signaling pathways. Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases