RESUMO

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson's disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies confirm the obtained structural model of the complex, eventually revealing the interaction site of CDNF and GRP78. Finally, mutating the key residues of CDNF mediating its interaction with GRP78 not only results in impaired binding of CDNF but also abolishes the neuroprotective activity of CDNF-derived peptides in mesencephalic neuron cultures. These results suggest that the molecular interaction with GRP78 mediates the neuroprotective actions of CDNF and provide a structural basis for development of next generation CDNF-based therapeutic compounds against neurodegenerative diseases.

Assuntos

RESUMO

Despite significant progress in recent years, the cleavage of unstrained C(sp(3))-C(sp(3)) bonds remains challenging. A C-C coupling and cleavage reaction in a PC(sp(3))P iridium pincer complex is mechanistically studied; the reaction proceeds via the formation of a carbene intermediate and can be described as a competition between α-hydrogen and α-alkyl elimination; the latter process was observed experimentally and is an unusual way of C(sp(3))-C(sp(3)) bond scission, which has previously not been studied in detail. Mechanistic details that are based upon kinetic studies, activation parameters, and DFT calculations are also discussed. A full characterization of a C-C agostic intermediate is presented.

Assuntos

RESUMO

A cyclohexyl-based POC sp 3OP pincer ligand (POC sp 3OP=cis-1,3-bis(di-tert-butylphosphinito)cyclohexyl) cyclometalates with nickel to generate a series of new POC sp 3OP-supported Ni(II) complexes, including the halide, hydride, methyl, and phenyl species. trans-[NiCl{cis-1,3-bis(di-tert-butylphosphinito)cyclohexane}], [(POC sp 3OP)NiCl] (1 a) and the analogous bromide complex (1 b) were synthesized and fully characterized by NMR spectroscopy and X-ray crystallography. Cyclic voltammetry measurements of 1 a and 1 b alongside their bis(phosphine) analogues [(PC sp 3P)NiCl] (2 a) and [(PC sp 3P)NiCl] (2 a) (PC sp 3P=cis-1,3-bis(di-tert-butylphosphino)cyclohexyl) indicate a reduced electron density at the metal center upon introducing electron-withdrawing oxygen atoms in the pincer arms. The methyl [(POC sp 3OP)NiMe] (3) and phenyl [(POC sp 3OP)NiPh] (4) complexes were formed from 1 a by reaction with the corresponding organolithium reagents. 1 a also reacts with LiAlH4 to give the hydride complex [(POC sp 3OP)NiH] (5). The methyl complex 3 reacts with phenyl acetylene to give the acetylide complex [(POC sp 3OP)NiCCPh] (6). The reactivity of compounds 3-5 towards CO2 was studied. The hydride complex 5 and the methyl complex 3 both underwent CO2 insertion to form the formate species [(POC sp 3OP)NiOCOH] (7) and acetate species [(POC sp 3OP)NiOCOCH3 ] (8), respectively, although with a higher barrier of insertion in the latter case. Compound 4 was unreactive towards CO2 even at elevated temperatures. Complexes 3-8 were all characterized by NMR spectroscopy and X-ray crystallography.

RESUMO

The title compound, [Ni2(C22H46P2O2)2(CO)2], is located about a centre of inversion with the Ni(0) atom within a distorted trigonal-planar geometry. The cyclo-hexyl rings are in the usual chair conformation with the 1,3-cis substituents equatorially oriented. No specific inter-molecular inter-actions are noted in the crystal packing. A region of disordered electron density, most probably a disordered deuterobenzene solvent molecule, was treated using the SQUEEZE routine in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155]. Its formula mass and unit-cell characteristics were not taken into account during refinement.

RESUMO

The substitution reaction of trans-[Rh(Cl)(CO)(SbPh3)2] (1) with tris(2,4-di-tert-butylphenyl)phosphite (2,4-TBPP) to form trans-[Rh(Cl)(CO)(2,4-TBPP)2] (4) in two consecutive steps has been investigated by UV-vis stopped-flow spectrophotometry. The experiments were performed in dichloromethane and in ethyl acetate, at 298 K and 268 K respectively for the first reaction step, and for the second reaction step over a temperature range from 278 to 313 K in both solvents. The first step is very fast (up to 1630 s(−1)) and on the limit of what is observable with the stopped-flow technique. Introduction of the five-coordinate complex trans-[Rh(Cl)(CO)(SbPh3)3] (2) in equilibrium with (1), by adding an excess SbPh3, led to a significant decrease in overall reaction rate for the formation of the intermediate trans-[Rh(Cl)(CO)(SbPh3)2(2,4-TBPP)] (3). Activation parameters for the second substitution reaction, in which 3 is converted to 4, has been determined as ΔH‡ = 22.85 ± 0.17 and 28.38 ± 0.10 kJ mol(−1) and ΔS‡ = −144.7 ± 0.6 and −100.9 ± 0.4 J mol(−1) K(−1) for CH2Cl2 and EtOAc respectively, supporting an associative pathway. A strongly coordinating solvent promotes both reactions. In all reaction steps a strong tendency for stibines to promote 5-coordinated, fairly stable intermediates is manifested.

Assuntos