Cleavage of the peptide bond of beta-alanyl-L-histidine (carnosine) induced by a Co(III)-amine complexes: reaction, structure and mechanism

Cleavage of the peptide bond occurs when beta]-alanyl-L-histidine (carnosine) reacts with [Co(tren)Cl2]+ (tren = tris(2-aminoethyl)amine) to give [Co(tren)(histidine)](2+) 1 and [Co(tren)(beta-alanine)](2+) 2. [Co(tren)(histidine)](2+) 1 crystallizes in the enantiomorphic space group P2(1)2(1)2(1) and 2 crystallizes in the P2(1)/c space group. The mechanism of the cleavage reactions were studied in detail for the precursor [Co(tren)Cl2]+ and [Co(trien)Cl2]+, which convert into [Co(tren)(OH)2]+/[Co(tren)(OH)(OH2)]2+ and [Co(trien)(OH)2]+/[Co(trien)(OH)(OH2)]2+ in water at basic pH (trien = 1,4,7,10-tetraazadecane). At a slightly basic pH, the initial coordination of the substrate (beta-alanyl-L-histidine) is by the carboxylate group for the reaction with [Co(tren)Cl2]+. This is followed by a rate-limiting nucleophilic attack of the hydroxide group at the beta-alanyl-L-histidine carbonyl group. In a strongly basic reaction medium substrate, binding of the metal was through carboxylate and amine terminals. On the other hand, for the reaction between [cis-beta-Co(trien)Cl2]+ and beta-alanyl-L-histidine, the initial coordination of the substrate takes place via an imidazole ring nitrogen, independently, and followed by a nucleophilic attack of the hydroxide group at the beta-alanyl-L-histidine carbonyl group. The circular dichroism spectrum for 1 suggests that a very small extent of racemization of the amino acid (L-histidine) takes place during the cleavage reaction between [Co(tren)Cl2]+ and beta-alanyl-L-histidine. Reaction between [cis-beta-Co(trien)Cl2]+ and beta-alanyl-L-histidine also causes cleavage of the peptide bond, producing a free beta-alanyl molecule and a cationic fragment [cis-alpha-Co(trien)(histidine)](2+) 3 that crystallizes in the optically active space group P2(1)2(1)2(1). Unlike the previous case an appreciable degree of racemization of the L-histidine takes place during the reaction between [cis-beta-Co(trien)Cl2]+ and beta-alanyl-L-histidine. Crystals containing L-histidine and D-histidine fragments in the [cis-alpha-Co(trien)(histidine)]2+ moiety were crystallographically documented by mounting a number of randomly selected crystals.     

Capillary gas chromatographic separation of C10–C12 secondary phenylalkanes on modified cyclodextrin stationary phases

The separation of isomers and enantiomers of branched C₁₀-C₁₂ phenylalkanes by gas chromatography on fused silica capillary columns coated with some modified β- and γ-cyclodextrins was studied. It was shown that the separation of positional isomers of C₁₀-C₁₂ phynylalkanes on modified cyclodextrin capillary columns is not better than that on a column coated with modified polyethylene glycol. Differences were found in the enantioselectivity of modified β- and γ-cyclodextrins for the separation of C₁₀-C₁₂ secondary phenylalkane enantiomers. While alkylderivatives of β-CDs resolve enantiomers of 3-phenylalkanes, alkyl derivatives of γ-CD resolve enantiomers of 2-phenylalkanes. Since shape selectivity factors of modified cyclodextrins have indicated no inclusion of the considered solutes in cyclodextrin cavities, enantioselective interactions most probably occur on the outer sphere of cyclodextrins.     

Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer’s disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 μs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity.     

Synthesis and Antiviral Properties against SARS-CoV-2 of Epoxybenzooxocino[4,3-b]Pyridine Derivatives

The COVID-19 pandemic is ongoing as of mid-2022 and requires the development of new therapeutic drugs, because the existing clinically approved drugs are limited. In this work, seven derivatives of epoxybenzooxocinopyridine were synthesized and tested for the ability to inhibit the replication of the SARS-CoV-2 virus in cell cultures. Among the described compounds, six were not able to suppress the SARS-CoV-2 virus’ replication. One compound, which is a derivative of epoxybenzooxocinopyridine with an attached side group of 3,4-dihydroquinoxalin-2-one, demonstrated antiviral activity comparable to that of one pharmaceutical drug. The described compound is a prospective lead substance, because the half-maximal effective concentration is 2.23 μg/μL, which is within a pharmacologically achievable range.     

Pulsed Nd:YAG laser welding of AISI 304 to AISI 420 stainless steels

The technique to weld AISI 304 stainless steel to AISI 420 stainless steel with a pulsed Nd:YAG laser has been investigated. The main objective of this study was to determine the influence of the laser beam position, with respect to the joint, on weld characteristics. Specimens were welded with the laser beam incident on the joint and moved 0.1 and 0.2 mm on either side of the joint. The joints were examined in an optical microscope for cracks, pores and to determine the weld geometry. The microstructure of the weld and the heat affected zones were observed in a scanning electron microscope. An energy dispersive spectrometer, coupled to the scanning electron microscope, was used to determine variations in (weight %) the main chemical elements across the fillet weld. Vickers microhardness testing and tensile testing were carried out to determine the mechanical properties of the weld. The results of the various tests and examinations enabled definition of the best position for the incident laser beam with respect to the joint, for welding together the two stainless steels.     

Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus

The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O-methyltransferase (nsp16) enzyme that is crucial for effective translation of viral RNA and virus replication. For methylation of substrates, nsp16 utilizes S-adenosyl methionine (SAM). Binding of a small molecule in the protein site where SAM binds can disrupt the synthesis of viral proteins and, as a result, the replication of the virus. Here, we performed high-throughput docking into the SAM-binding site of nsp16 for almost 40 thousand structures, prepared for compounds from three libraries: Enamine Coronavirus Library, Enamine Nucleoside Mimetics Library, and Chemdiv Nucleoside Analogue Library. For the top scoring ligands, semi-empirical quantum-chemical calculations were performed, to better estimate protein–ligand binding enthalpy. Relying upon the calculated binding energies and predicted docking poses, we selected 21 compounds for experimental testing.     

Unexpected formation of dinaphthoaza-17-crown-5 ether containing γ-aminopiperidine subunit

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Statistical inference for Vasicek-type model driven by Hermite processes

Let $Z$ denote a Hermite process of order $q\ge 1$ and self-similarity parameter $H\in (\frac{1}{2},1)$. This process is $H$-self-similar, has stationary increments and exhibits long-range dependence. When $q=1$, it corresponds to the fractional Brownian motion, whereas it is not Gaussian as soon as $q?2$. In this paper, we deal with a Vasicek-type model driven by $Z$, of the form $d{X}_t=a(b?X_t)dt+d{Z}_t$. Here, $a>0$ and $b\in \mathbb{R}$ are considered as unknown drift parameters. We provide estimators for $a$ and $b$ based on continuous-time observations. For all possible values of $H$ and $q$, we prove strong consistency and we analyze the asymptotic fluctuations.     

Intermolecular interactions between natural humic substances and tricyclic antidepressants

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On the variety of triangles for a hyper-Kähler fourfold constructed by Debarre and Voisin

We study the similarities between the Fano varieties of lines on a cubic fourfold, a hyper-Kähler fourfold studied by Beauville and Donagi, and the hyper-Kähler fourfold constructed by Debarre and Voisin in [3]. We exhibit an analog of the notion of “triangle” for these varieties and prove that the 6-dimensional variety of “triangles” is a Lagrangian subvariety in the cube of the constructed hyper-Kähler fourfold.