Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer''s disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined ¹⁹F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrP^C in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer''s disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development.

A new approach combining virtual screening, ¹⁹F and STD NMR, and biochemical assays using hiPSC and targetting multiple pathways involving Aβ, PrP^C and Tau provides a more effective strategy for Alzheimer''s disease drug discovery than Aβ only approach.     

A new free recoverable and reusable mono-alkaloid-type ligand and its use in preparation of ethyl （2R,3S）-2,3-dihydroxy-3-phenylpropionate

A new free recoverable and reusable mono-alkaloid-type ligand has been synthesized by a simple method.With highly polar groups,the ligand can be recycled and reused eight times to prepare ethyl(2R,3S)-2,3-dihydroxy-3-phenylpropionate with high yield and ee via asymmetric dihydroxylation(AD) reaction.     

The step-wise assembly of an undecanuclear heterotrimetallic cyanide cluster

The step-wise assembly of the high nuclearity cluster, {[Ni(II)(H2O)5]6[Co(III)(tmphen)2]3[Fe(II)(CN)6]2}13+, is achieved by treating {[Co(tmphen)2]3[Fe(CN)6]2} with six equivalents of Ni(ClO4)2 in aqueous MeOH.     

Unexpected conversion of a hexacyanometallate to a homoleptic nitrile complex with triphenylborane substituents

The homoleptic, triphenylborane adduct of the hexacyanochromate anion was structurally characterized and found to be a product in which all six cyanide ligands have undergone isomerization to nitrile groups.     

New chromogens of the ferroin type-V Pyridylpyrimidines, bidiazines and other substituted derivatives of diazines

Spectrophotometric studies of the reactions of iron(II), copper(I) and cobalt(II) with 33 new compounds have demonstrated that the chromogenic properties of diazyl groups are inferior to those of triazyl or pyridyl groups when incorporated into the ferroin chromophore group. The metal complexes of the diazyl derivatives are less stable than those of the corresponding pyridyl and triazyl derivatives. Conditional formation constants of the iron(II) chelates of some representative diazyl derivatives indicate that pyridazyl groups impart greater stabilities than pyrimidyl or pyrazyl groups. Five of the new chromogens have structures that suggest they can chelate iron(II) without steric hindrance, either as bidentate or as terdenate ligands. Although the terdentate mode would ordinarily be expected, two of the five were found to act preferably as bidentate ligands.     

Figure-of-eight Shaped Metal-free Amide-containing Schiff-base Macrocycles and Two Dicobalt(III) Amide Complexes

Abstract

Two 36-membered (2+2) Schiff-base macrocycles have been prepared and characterised without the use of template ions or high dilution techniques. Rather, intramolecular hydrogen-bonding and π-π interactions promote the isolation of these “figure-of-eight” products in good yields. Two cobalt(III) complexes of the 18-membered (1+1) Schiff-base macrocycles are formed when cobalt(II) is used as a template. The structures of one “figure-of-eight' metal-free (2+2) macrocycle and of one dicobalt(III) complex of a (1+1) macrocycle, in which the cobalt centres are octahedral, are presented. [H₄L1tBu]₂: C₇₀H₇₀N₈O₉, space group P-1, a=7.747(1), b=17.106(3), c=23.662(4) å, α=104.83(3), β=95.86(3), γ=97.80(3)°, U=2972.4(8) å³, Z=2, D_c=1.30 g cm^?3, T=100K, 554 parameters, R1=0.072 [for 4137 reflections having F>4[(F)], wR₂=0.191 and goodness of fit 0.97 (for all 8343 independent F² data). [Co₂(L1tBu)(OAc)₂(pyridine)] 1.5DMF 0.5MeCN, C_47.5H₄₉N₇O9.5Co₂, space group P2(1)/n, a=13.067(2), b=26.071(4), c=14.023(3) å, β=93.02(1)°, U=4770.6(15) å³, Z=4, D_c=1.38 g cm^?3, T=168 K, 622 parameters, R1=0.075 [for 5233 reflections having F > 4[?F?], wR2=0.133 and good ness of fit 1.08 (for all 8512 independent F² data).