Probing Alzheimer's pathology: Exploring the next generation of FDDNP analogues for amyloid ß detection.

Fluorescent probes are a powerful tool for imaging amyloid ß (Aß) plaques, the hallmark of Alzheimer's disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aß fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aß- and Tau-aggregates. First, 1Ae had large Stokes shifts (138-213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aß fibrils in vitro (Kd = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aß1-42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aß plaques. The intermolecular interactions of fluorophores with Aß were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aß1-42 in cerebrospinal fluid or blood.

Fusion Position-Dependent Aromatic Transitions of Ligand Backbone Rings for Controlling the Redox Energetics of Photoredox Catalysts.

To reveal, quantify, and rationalize the effect of backbone π-extension on ligand redox activity, we studied the ground- and excited-state reduction potentials of eight ruthenium photoredox catalysts with the formula Ru(ppy)2L (L is the redox-active ligand of the bipyridine family) using density functional theory. Our research underlines the profound importance of the fusion position of backbone aromatic C6 rings on the redox activity of ligands in transition metal photoredox catalysts. Namely, certain fusion positions lead to the dearomatization of C6 rings in ligand-centered electron transfer events, resulting in a thermodynamic penalty equivalent to a half-volt negative shift in the reduction potential. Contrarily, the extent of backbone delocalization shows a minimal impact on redox energetics, which can be explained by the charge concentration at the nitrogen contact atoms in ligand-centered reductions. Grounded in Caulton's conceptual framework, we reaffirm the predictive potency of Lewis structures in ligand-centered redox energetics with qualitative and quantitative data. Our hypothesis regarding the effect of backbone ring dearomatization on redox energetics is further corroborated using magnetic and structure-based aromaticity indicators. Highlighting fusion-dependent dearomatization as a determining factor of ligand-centered electron transfer energetics, our findings hold implications for molecular-level design in advanced electroactive materials and catalysts.

Resonance and electrostatics making the difference in boron- and aluminum-halide structures and exchange reactivity.

The mechanism of the gas-phase halogen-exchange reaction between boron- and aluminum-halides (i.e., BX3 + BX3 and AlX3 + AlX3, X = F, Cl, or Br) was discovered using density functional theory. The reaction takes place via a two-step mechanism with the intermediacy of a diamond-core structure analogous to diborane. Good agreement was found between the simulated reaction features and experimental observations, which demonstrate slow kinetics and an equilibrium process for boron species and dimer formation in the case of aluminum-halides. This computational and theoretical study also reveals and quantifies the effect of resonance on the thermodynamic stability of the central intermediate and conceptualizes the extreme stability difference (∼50 kcal mol-1) between boron and aluminum diamond-core bridge structures. Through an interaction energy decomposition analysis in combination with electronic structure analyses, we revealed that, beyond the resonance stabilization in free boron-halides, superior electrostatics in aluminum-halides results in the different reactivities, i.e., dimer formation for the latter species whereas substituent exchange for the former ones.