Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure‐Based Design of Inhibitors for Trypsin‐Like Serine Proteases

In the absence of X‐ray data, the exploration of compound binding modes continues to be a challenging task. For structure‐based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin‐like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi‐ and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations. Asymmetric bisbenzamidines were used as starting points for a multistage and structure‐guided optimization. A series of 24 final compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase‐2, thrombin and factor Xa. This study underlines the relevance of ligand symmetry for chemical biology.     

Supramolecular photochirogenesis with biomolecules. Mechanistic studies on the enantiodifferentiation for the photocyclodimerization of 2-anthracenecarboxylate mediated by bovine serum albumin

Photophysics and photochemistry of 2-anthracenecarboxylate (AC) bound to bovine serum albumin (BSA) were investigated in detail for the first time by electronic absorption, circular dichroism (CD), steady-state and time-resolved fluorescence, fluorescence quenching, and product analysis studies. Through the spectroscopic investigations, it was revealed that the four independent binding pockets of BSA, which are known to accommodate 1, 3, 2, and 3 AC molecules in the order of decreasing affinity, are distinctly different in hydrophobicity, chiral environment, and accessibility. Interestingly, AC bound to site 1 gave highly structured fluorescence with dual lifetimes of 4.8 and 2.1 ns in an intensity ratio of 3:2, which may be assigned to the existence of two positional or orientational isomers within the very hydrophobic site 1. In contrast, the lifetime of AC in site 2 was much longer (13.3 ns), and ACs in sites 3 and 4 have broader fluorescence spectra with lifetimes that were practically indistinguishable from that in bulk water (15.8 ns). Although each of sites 2-4 simultaneously binds multiple AC molecules, no CD exciton coupling or static fluorescence quenching was detected, indicating that ACs bound to each site are not in close proximity to each other. Quenching studies with nitromethane further confirmed the significant difference in accessibility among the binding sites; thus, ACs bound to sites 1 and 2 are highly protected from the attack of the quencher, affording 32 and 10 times smaller rate constants than that for free AC in water. Product studies in the presence and absence of nitromethane more clearly revealed the photochirogenic performance of each binding site. Although the addition of nitromethane did not greatly alter the product distribution, the enantiomeric excesses (ee's) of chiral cycloadducts 2 and 3 were critically manipulated by selectively retarding the photoreaction occurring at the more accessible binding sites. Thus, the highest ee of 38% was obtained for 2 in the presence of 18 mM nitromethane, while the highest ee of 58% was attained for 3 in the absence of nitromethane, both at [AC]/[BSA]=3.6.     

Template-controlled reactivity: Following nature's way to design and construct metal-organic polyhedra and polygons

We show how a template-controlled reaction performed in the organic solid state can be used to construct a molecule that functions as an organic building unit of both a metal-organic polyhedron and polygon. The template is a small organic molecule that organizes two olefins via hydrogen bonds for a [2+2] photodimerization. The process of utilizing a molecule to build a molecule that is subsequently used for self-assembly is inspired by the general two-step process of template-directed synthesis and self-assembly of Nature that is used to construct large, functional self-assembled structures.     

The influence of daylight exposure on platelet 5-HT levels in patients with major depression and schizophrenia

Platelet serotonin (5-HT) can be used as a limited, peripheral model for the central 5-HT synaptosomes. Altered platelet 5-HT concentrations have been associated with psychiatric disorders like depression and schizophrenia. The aim of the present study was to compare platelet 5-HT concentrations during long, medium and short period of natural daylight exposure in a large number of medication-free male and female schizophrenic and depressed patients and sex-matched healthy controls. Platelet 5-HT concentration was determined spectrofluorimetrically in 240 (97 female, 143 male) schizophrenic and 258 (153 female, 105 male) nonpsychotic, nonsuicidal depressed medication-free patients and 328 (149 women, 179 men) healthy subjects during periods with short (<12), long (>12) and medium (average 12) hours of the natural daylight. Platelet 5-HT concentration was significantly lower in women compared to men in all groups. Healthy male subjects had significantly higher (p=0.011) platelet 5-HT concentrations during long compared to medium period. There were no significant differences (p>0.05) in platelet 5-HT concentration between different periods in healthy women. The significant increase in platelet 5-HT values were found in female (p=0.01) and male (p=0.029) depressed patients during long compared to short period. There were no significant associations between platelet 5-HT concentrations and different periods in both male and female schizophrenic patients. The results indicate the sex-related differences in the serotonergic system. The alterations of platelet 5-HT concentrations, observed across period with different durations of daylight exposure, point to a direct or indirect effect of light on peripheral 5-HT system that could be related to different sensitivity of the pineal gland to light and/or melatonin influence on 5-HT metabolism.     

Sustainability of microporous polymers and their applications

Microporous polymers (MPs) are studied for their intriguing chemistry and physics as well as their potential application in catalytic transformations, gas-separation processes, water purification and so on. Here, we critically review MPs with respect to the sustainability aspects of their synthesis as well as their applications that have sustainable character. Some MPs have been synthesized from monomers derived from biomass resources, but there is certainly a large potential for further developments. There are also opportunities to improve the sustainability of MP synthesis in terms of the use of solvents, catalysts, and related aspects. The applications of MPs in processes related to sustainability depend upon multiple properties. A rich and flexible chemistry is important to applications as catalysts for, among other useful reactions, the photoreduction of CO₂ and selective oxidation. The (ultra)micropore volume of MPs are crucial in gas-separation applications such as CO₂ capture, and the chemisorption of CO₂ on MP-tethered alkylamines could offer a means to remove that gas from dilute mixtures. When it comes to the storage of H₂ and CH₄ in MPs for onboard use in fuel cell or biogas cars, volumetric capacity is paramount, meaning that the density of the MPs must be considered. Finally, for use in separation and purifications from liquid mixtures (aqueous or hydrocarbon-based), crosslinked MPs are more limited than the solution-processable MPs that can be more easily processed into films and membranes.     

An Organoruthenium Anticancer Agent Shows Unexpected Target Selectivity For Plectin

Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, using an integrated proteomics-based target-response profiling approach as a potent hypothesis-generating procedure, we found an unexpected target selectivity of a ruthenium(arene) pyridinecarbothioamide (plecstatin) for plectin, a scaffold protein and cytolinker, which was validated in a plectin knock-out model in vitro. Plectin targeting shows potential as a strategy to inhibit tumor invasiveness as shown in cultured tumor spheroids while oral administration of plecstatin-1 to mice reduces tumor growth more efficiently in the invasive B16 melanoma than in the CT26 colon tumor model.     

Synthesis and Antiviral Evaluation of (1,4-Disubstituted-1,2,3-Triazol)-(E)-2-Methyl-but-2-Enyl Nucleoside Phosphonate Prodrugs

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-(E)-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j, a hexadecyloxypropyl (HDP)/(isopropyloxycarbonyl-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 μM, without significant cytotoxicity (IC₅₀ = 66.4 μM in HepG2 cells, IC₅₀ = 43.1 μM in HepG2 cells) at 10 μM.     

Nonlinear frequency response analysis: a recent review and perspectives

The nonlinear frequency response analysis (NFRA) can be seen as an extension of electrochemical impedance spectroscopy. NFRA gives a full and detailed representation of the system response and can establish a connection between model parameters and the experimentally observed phenomena. In this article, different theoretical NFRA approaches and the most recent application examples are discussed. A simple electrochemical example is used to showcase the benefits and disadvantages of analyzing the system response by using different approaches. In addition, it was shown how to extract experimental harmonic values and analyze them.     

Nutritional Value and Preventive Role of Nigella sativa L. and Its Main Component Thymoquinone in Cancer: An Evidenced-Based Review of Preclinical and Clinical Studies

In recent times, scientific attention has been paid to different foods and their bioactive components for the ability to inhibit the onset and progress of different types of cancer. Nigella sativa extract, powder and seed oil and its main components, thymoquinone and α-hederin, have showed potent anticancer and chemosensitizing effects against various types of cancer, such as liver, colon, breast, renal, cervical, lung, ovarian, pancreatic, prostate and skin tumors, through the modulation of various molecular signaling pathways. Herein, the purpose of this review was to highlight the anticancer activity of Nigella sativa and it constitutes, focusing on different in vitro, in vivo and clinical studies and projects, in order to underline their antiproliferative, proapoptotic, cytotoxic and antimetastatic effects. Particular attention has been also given to the synergistic effect of Nigella sativa and it constitutes with chemotherapeutic drugs, and to the synthesized analogs of thymoquinone that seem to enhance the chemo-sensitizing potential. This review could be a useful step towards new research on N. sativa and cancer, to include this plant in the dietary treatments in support to conventional therapies, for the best achievement of therapeutic goals.