Peptide‐Based Molecular Strategies To Interfere with Protein Misfolding,Aggregation, and Cell Degeneration

Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell‐ and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. So far, however, only one of the numerous anti‐amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry “tools” to design, develop, and discover peptide‐based molecules as anti‐amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1) the oldest and most common strategy, based on molecular recognition elements of amyloid self‐assembly, and 2) a more recent approach, based on cross‐amyloid interactions. We discuss why peptide‐based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti‐amyloid drugs as well as valuable tools for deciphering amyloid‐mediated cell damage and its link to disease pathogenesis.     

Rare-Earth Metal Complexes of the Antibacterial Drug Oxolinic Acid: Synthesis,Characterization, DNA/Protein Binding and Cytotoxicity Studies

“Drug repositioning” is a current trend which proved useful in the search for new applications for existing, failed, no longer in use or abandoned drugs, particularly when addressing issues such as bacterial or cancer cells resistance to current therapeutic approaches. In this context, six new complexes of the first-generation quinolone oxolinic acid with rare-earth metal cations (Y³⁺, La³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺) have been synthesized and characterized. The experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms; these findings are supported by DFT (density functional theory) calculations for the Sm³⁺ complex. The cytotoxic activity of the complexes, as well as the ligand, has been studied on MDA-MB 231 (human breast adenocarcinoma), LoVo (human colon adenocarcinoma) and HUVEC (normal human umbilical vein endothelial cells) cell lines. UV-Vis spectroscopy and competitive binding studies show that the complexes display binding affinities (K_b) towards double stranded DNA in the range of 9.33 × 10⁴ − 10.72 × 10⁵. Major and minor groove-binding most likely play a significant role in the interactions of the complexes with DNA. Moreover, the complexes bind human serum albumin more avidly than apo-transferrin.     

Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.     

On the capacitive behavior of silicon electrodes modified with ultrathin hydrophobic polymer brushes

Journal of Solid State Electrochemistry - The modification of a silicon surface with ultrathin poly(styrene) brushes, obtained by grafting-from, results in a dramatic increase in capacitance as...     

Efficient synthesis of tetrazole derivatives of cytisine using the azido-Ugi reaction

The azido-Ugi reaction with natural alkaloid cytisine was investigated. It was demonstrated that the reaction could be performed with various carbonyls (both aldehydes and ketones) and isocyanides. The transformation proceeded under mild conditions in methanol using TMSN3 as a source of hydrazoic acid to give target tetrazole derivatives of cytisine in up to 98% yield. The diastereoselectivity of this reaction was studied using both aliphatic and aromatic aldehydes. A family of tetrazole derived cytisine compounds was prepared. Selective deprotection of tetrazoles was elaborated to synthesize the corresponding NH-tetrazoles.     

Solution of Fractional Quadratic Programs on the Simplex and Application to the Eigenvalue Complementarity Problem

Journal of Optimization Theory and Applications - In this paper, we introduce an implementation of Dinkelbach’s algorithm for computing a global maximum of a fractional linear quadratic...     

Computational Analysis of a Radiofrequency Knee Coil for Low-Field MRI Using FDTD

Magnetic resonance imaging (MRI) is essential for the diagnosis and treatment of musculoskeletal conditions. Low-field (<0.5T) imaging is a cost-effective alternative to more expensive high-field strength imaging due to the inexpensive setting, greater patient comfort and better safety profile. On the other hand, if compared with high-field body scanners, the low-field scanners produce poor-quality images with lower signal-to-noise ratio. Especially in low-field MR, receiver coil performance plays a significant role in image quality. Coil performance is generally evaluated using classical electromagnetic theory, but when the coil is loaded with a sample, an analytical solution is extremely difficult to derive, so that a trial-and-error approach is often followed. Numerical methods have been proposed in literature as good alternatives to predict MRI coil performance. In this study the performance of a knee coil for low-field (0.5 T) MR scanners is analyzed using workbench tests and numerical simulation with a software program based on the finite difference time domain method. Parameter performances measured using the classical workbench test are compared with those obtained using numerical simulations. Finally, the knee coil performance is validated with images acquired in a commercial low-field MR system.     

Optical,Dielectric, and Conduction Properties of New Phosphorus-Modified Polysulfones

New phosphorus-modified polysulfones with different substitution degrees, obtained from chloromethylated polysulfones, were analyzed in terms of their optical, dielectric, and conduction properties. In order to obtain the optical parameters, the approach proposed by Tauc for amorphous semiconductors was used.^{[ 23} Tauc, J., Menth, A. and Wood, D. L. 1970. Optical and magnetic investigations of the localized states in semiconducting glasses. Phys. Rev. Lett., 25: 749–752. [Crossref] , [Google Scholar] ^{, 24} Tauc, J. and Menth, A. 1972. States in the gap. J. Non-Cryst. Solids, 8–10: 569–585. [Crossref] , [Google Scholar] ^] The determined parameters were found to be related to the influence of the polymer chain structure and the history of films’ preparations. The temperature and frequency dependence of dielectric constant and dielectric relaxation were investigated by AC-dielectric measurements. The nature of the relaxation mechanisms was established on the basis of the dielectric measurement results. The samples displayed two sub-glass relaxations, i.e. γ relaxation – where the activation energy changes insignificantly with the substitution degree, and β relaxation – with higher apparent activation energy for lower substitution degrees. The results obtained from Tauc's law and AC-conduction studies indicated that the conduction mechanism in the phosphorus-modified polysulfone was due to electronic hopping, and that a model based on the energy bandgap representation could be suitable for explaining the temperature dependence of electrical conductivity.