Conformation of Pyroglutamated Amyloid β (3-40) and (11-40) Fibrils - Extended or Hairpin?

Amyloid β (Aβ) is a hallmark protein of Alzheimer's disease. One physiologically important Aβ variant is formed by initial N-terminal truncation at a glutamic acid position (either E or E), which is subsequently cyclized to a pyroglutamate (either pE or pE). Both forms have been found in high concentrations in the core of amyloid plaques and are likely of high importance in the pathology of Alzheimer's disease.

Exploring the potential of tamoxifen-based copper(ii) dichloride in breast cancer therapy.

For decades, tamoxifen-based hormone therapy has effectively addressed oestrogen receptor positive (ER+) luminal A breast cancer. Nonetheless, the emergence of tamoxifen resistance required innovative approaches, leading to hybrid metallodrugs with several therapeutic effects besides the inhibition of oestrogen receptor α (ERα). Drawing inspiration from tamoxifen metabolite structures (4-hydroxytamoxifen and 4,4'-dihyroxytamoxifen), a phenyl ring was replaced by a bidentate 2,2'-bipyridine donor moiety to give 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (L), enabling coordination of bioactive transition metal compounds such as copper(ii) dichloride, yielding [CuCl(μ-Cl)(L-κ,')] (1).

Correction: Kazimir et al. Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes. 2023, , 682.

In the original publication [...

Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes.

The luminal A-subtype of breast cancer, where the oestrogen receptor α (ERα) is overexpressed, is the most frequent one. The prodrug tamoxifen () is the clinically used agent, inhibiting the ERα activity via the formation of several active metabolites, such as 4-hydroxytamoxifen () or 4,4'-dihydroxytamoxifen (). In this study, we present the tamoxifen derivative 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (), which was combined with platinum or palladium dichloride, the former a well-known scaffold in anticancer treatment, to give [PtCl(-κ,')] () or [PdCl(-κ,'] ().

How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β.

Amyloid fibrils represent the structural endpoint on the energetic (mis)folding landscape of very many proteins. Physiologically, amyloid fibrils are observed as a characteristic hallmark in misfolding diseases often associated with degenerative and neurodegenerative disorders. In the beginning of the scientific discussion, the focus is laid on the fibrillar state, but over the time it becomes increasingly clear that low molecular weight and transient aggregates are of crucial importance for pathological mechanisms.

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized Xe NMR.

G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and label this cysteine with a probe for detection. Here, the application of NMR of hyperpolarized Xe for the detection of the conformational states of human neuropeptide Y2 receptor is introduced.

Predicting H NMR acyl chain order parameters with graph neural networks.

H NMR order parameters of the acyl chain of phospholipid membranes are an important indicator of the effects of molecules on membrane order, mobility, and permeability. So far, the evaluation procedures are case-by-case studies for every type of small molecule with certain types of membranes. Rapid screening of the effects of a variety of drugs would be invaluable if it were possible.

Peptide backbone modifications of amyloid β (1-40) impact fibrillation behavior and neuronal toxicity.

Fibril formation of amyloid β (Aβ) peptides is one of the key molecular events connected to Alzheimer's disease. The pathway of formation and mechanism of action of Aβ aggregates in biological systems is still object of very active research. To this end, systematic modifications of the Phe-Leu hydrophobic contact, which has been reported in almost all structural studies of Aβ fibrils, helps understanding Aβ folding pathways and the underlying free energy landscape of the amyloid formation process.

Preparing (Metalla)carboranes for Nanomedicine.

"There's plenty of room at the bottom" (Richard Feynman, 1959): an invitation for (metalla)carboranes to enter the (new) field of nanomedicine. For two decades, the number of publications on boron cluster compounds designed for potential applications in medicine has been constantly increasing. Hundreds of compounds have been screened in vitro or in vivo for a variety of biological activities (chemotherapeutics, radiotherapeutics, antiviral, etc.

2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes.

Investigations on the antitumor activity of metallacarboranes are sparse in the literature and limited to a handful of ruthena- and molybdacarboranes. In this study, the molybdacarborane fragment [3-(CO) -closo-3,1,2-MoC B H ] was combined with a vector molecule, inspired by the well-known drug tamoxifen or 4,4'-dihydroxytamoxifen (TAM-diOH). The molybdacarborane derivative [3,3-{4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine-κ N,N'}-3-(CO) -closo-3,1,2-MoC B H ] (10), as well as the ligand itself 4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (6) showed cytotoxic activities in the low micromolar range against breast adenocarcinoma (MDA-MB-231, MDA-MB-361 and MCF-7), human glioblastoma (LN-229) and human glioma (U-251) cell lines.

Spectroscopic and Electronic Properties of Molybdacarborane Complexes with Non-innocently Acting Ligands.

The molybdacarboranes [3-{L-κ N,N}-3-(CO) -closo-3,1,2-MoC B H ] (L=2,2'-bipyridine (2,2'-bpy, 1 a) or 1,10-phenanthroline (1,10-phen, 1 b)) incorporating well-known potentially non-innocent ligands (CO, 2,2'-bpy, 1,10-phen) and the "non-spectator" nido-carborane ([η -C B H ] ) ligand were prepared and fully characterised. High-resolution mass spectrometry, single-crystal X-ray diffraction methods, spectroscopy (IR, (resonance) Raman, NMR), cyclic voltammetry and spectroelectrochemistry (electrochemical properties) were supported by theoretical investigations of the electronic structure (DFT, CAS-SCF, TD-DFT).

12-Vertex Zwitterionic Bis-phosphonium-nido-carborates through Ring-Opening Reactions of 1,2-Diphosphetanes.

Carborane-substituted 1,2-diphosphetanes (Ia,b) react with elemental lithium in THF with cleavage of the P-P bond to give a deep red solution from which, in the case of Ia, red crystals of a lithiated intermediate, [{1-Li(THF)PtBu-6-PtBu-4,1,6-closo-Li(THF)C B H }{Li(THF) }] ⋅2 THF (2 a), are obtained. The compound is dimeric, C -symmetric and contains six lithium and four phosphorus atoms. Two lithium atoms cap the six-membered C B faces, resulting in two 13-vertex closo-clusters (according to Wade's rules) with docosahedral geometry.

Antiproliferative activity of (η-arene)ruthenacarborane sandwich complexes against HCT116 and MCF7 cell lines.

Three [(η-arene)RuCBH] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-CH (4)) were synthesised according to modified literature procedures and fully characterised. 2-4 were found to be moderately active against two types of tumour cell lines (HCT116 and MCF7), with IC values in the low micromolar range. However, viability of normal, healthy cells (MRC-5 cell line, MLEC and mouse macrophages) was not affected by treatment with 2-4, indicating high selectivity of the metallacarborane complexes towards tumour cell lines, compared to the unselective antitumour agent cisplatin and other potential Ru drugs.

C-Symmetric P,N Ligands Derived from Carborane-Based Diphosphetanes: Synthesis and Coordination Chemistry.

Racemic carborane-based bisphosphanes were obtained by dismutation reactions between a carborane-based diphosphetane and diaryl dichalogenides. NMR spectroscopic and theoretical studies revealed a two-step mechanism explaining the high stereoselectivity of these reactions. The coordination chemistry of the multidentate P,N ligands 6c and 6d in copper(I) and silver(I) complexes was studied.

Activation of CO by Hydrogenated Magnesium(I) Dimers: Sterically Controlled Formation of Ethenediolate and Cyclopropanetriolate Complexes.

This study details the formal hydrogenation of two magnesium(I) dimers {(Nacnac)Mg}2 (Nacnac = [{(C6H3R2-2,6)NCMe}2CH](-); R = Pr(i) ((Dip)Nacnac), Et ((Dep)Nacnac)) using 1,3-cyclohexadiene. These reactions afford the magnesium(II) hydride complexes, {(Nacnac)Mg(μ-H)}2. Their reactions with excess CO are sterically controlled and lead cleanly to different C-C coupled products, viz.

Two-coordinate hydrido-germylenes.

The first structurally characterised two-coordinate hydrido-germylenes, :Ge(H)L (L = -N(Ar){Si(OBu)}, Ar = C6H2{C(H)Ph2}2R-2,6,4; R = Pr(i) ((tBuO)L(†)), Me ((tBuO)L*)), have been prepared, and their dimerisation shown to be thermodynamically unfavourable, largely due to the extreme steric bulk of their amide ligands.