Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro models.

Alzheimer's disease (AD) is a neurological disease of confusing causation with no cure or prevention available. The definitive diagnosis is made postmortem, in part through the presence of amyloid-beta plaques in the brain tissue, which can be done with the small molecule thioflavin-T (ThT). Plaques are also found to contain elevated amounts of metal ions Cu(ii) and Zn(ii) that contribute to the neurotoxicity of amyloid-beta (Aß). In this paper, we report in silico, in vitro, and ex vivo studies with ThT-derived metal binders 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT) and their respective iodinated counterparts, HBXI and HBTI. They exhibit low cytotoxicity in a neuronal cell line, potential blood-brain barrier penetration, and interaction with Aß fibrils from senile plaques present in human and transgenic mice AD models. Molecular modelling studies have also been undertaken to understand the prospective ligand-Aß complexes as well as to rationalize the experimental findings. Overall, our studies demonstrate that HBX, HBT, HBXI, and HBTI are excellent agents for future use in in vivo models of AD, as they show in vitro efficacy and biological compatibility. In addition to this, we present the glycosylated form of HBX (GBX), which has been prepared to take advantage of the benefits of the prodrug approach. Overall, the in vitro and ex vivo assays presented in this work validate the use of the proposed ThT-based drug candidate series as chemical tools for further in vivo development.

Pairwise alignment of chromatograms using an extended Fisher-Rao metric.

A conceptually new approach for aligning chromatograms is introduced and applied to examples of metabolite identification in human blood plasma by liquid chromatography-mass spectrometry (LC-MS). A square-root representation of the chromatogram's derivative coupled with an extended Fisher-Rao metric enables the computation of relative differences between chromatograms. Minimization of these differences using a common dynamic programming algorithm brings the chromatograms into alignment. Application to a complex sample, National Institute of Standards and Technology (NIST) Standard Reference Material 1950, Metabolites in Human Plasma, analyzed by two different LC-MS methods having significantly different ranges of elution time is described.

Synthesis, spectroscopic characterization, and crystal structure of the bimetallic complex [Ni2(mu-CO)(CO)2(mu-NH(PPh2)2)2].

The dinuclear Ni(0) complex [Ni2(mu-CO)(CO)2(mu-dppa)2] (1; dppa = bis(diphenylphosphino)amine) was synthesized by two routes in good yield. Complex 1 has a triclinic crystal system and P1 space group, with a = 13.009(1) A, b = 13.063(2) A, c = 14.664(2) A, alpha = 79.91(1) degrees, beta = 79.96(1) degrees, gamma = 71.32(1) degrees, and Z = 2. The structure of this compound exhibits two mu-coordinated dppa ligands in a cis, cis arrangement. Nickel atoms are at a 2.5824(7) A distance. Theoretical calculations predict a 0.39 bond order between metal atoms. The cyclic voltammograms show two quasi-reversible redox pairs, which correspond to the successive oxidation of the metal centers. The dinuclear complex described absorbs carbon monoxide, yielding a mixture of nickel carbonyl compounds.