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Molecular dynamics with orientational constraints (MDOC) simulations use NMR parameters as tensorial constraints in the stereochemical analysis of small molecules. 13C-31P Residual dipolar couplings-aided MDOC simulations of small phosphorus molecules determined the relative configurations of rigid molecules after including 3JH-H-couplings as additional constraints. However, flexible molecules remain a problem.
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Residual dipolar couplings (RDCs) are employed in NMR analysis when conventional methods, such as J-couplings and nuclear Overhauser effects (NOEs) fail. Low-energy (optimized) conformers are often used as input structures in RDC analysis programs. However, these low-energy structures do not necessarily resemble conformations found in anisotropic environments due to interactions with the alignment medium, especially if the analyte molecules are flexible. Considering interactions with alignment media in RDC analysis, we developed and evaluated a molecular docking-based approach to generate more accurate conformer ensembles for compounds in the presence of the poly-γ-benzyl-L-glutamate alignment medium. We designed chiral phosphorus-containing compounds that enabled us to utilize 31P NMR parameters for the stereochemical analysis. Using P3D/PALES software to evaluate diastereomer discrimination, we found that our conformer ensembles outperform moderately the standard, low-energy conformers in RDC analysis. To further improve our results, we (i) averaged the experimental values of the molecular docking-based conformers by applying the Boltzmann distribution and (ii) optimized the structures through normal mode relaxation, thereby enhancing the Pearson correlation factor R and even diastereomer discrimination in some cases. Nevertheless, we presume that significant differences between J-couplings in isotropic and in anisotropic environments may preclude RDC measurements for flexible molecules. Therefore, generating conformer ensembles based on molecular docking enhances RDC analysis for mildly flexible systems while flexible molecules may require applying more advanced approaches, in particular approaches including dynamical effects.
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Herein, we investigate the structure-property relationships in a new series of benzothiazole based unsymmetrical hexafluorocyclopentene dithienylethenes (DTEs) and compare the results with the known facts for symmetric diarylethenes (DAEs). We reveal high photocyclization efficiency resulting from a significant shift of ground state equilibrium to the antiparallel conformation and a barrierless excited state pathway to conical intersection, which remains unperturbed even in polar solvents for most of the prepared DTEs. Furthermore, we uncover that the rate of back thermal cycloreversion correlates clearly more with the central C-C bond-length in the transition state than with the central C-C bond-length in the ground state of the cyclic form. Finally, our detailed vibrational spectral analysis of studied DTEs points out significant changes in Raman and infrared spectra during photoswitching cycles which pave the way for a non-destructive readout of stored information.
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Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ' efficacy and safety no longer justify its use as a first-line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine-modified KTZ derivatives and we evaluated their inâ vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24â times more potent against Aspergillus flavus and 8â times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100â µM. Derivative 6 had 9- and 7-fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC50 values. Combined, our findings will foster further research of piperazine-modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.
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Antifúngicos , Cetoconazol , Cetoconazol/farmacologia , Cetoconazol/química , Antifúngicos/farmacologia , Antifúngicos/química , AzóisRESUMO
Stimulator of interferon genes (STING) is an adaptor protein of the cGAS-STING signaling pathway involved in the sensing of cytosolic DNA. It functions as a receptor for cyclic dinucleotides (CDNs) and, upon their binding, mediates cytokine expression and host immunity. Besides naturally occurring CDNs, various synthetic CDNs, such as ADU-S100, have been reported to effectively activate STING and are being evaluated in clinical trials for the treatment of cancer. Here, we describe the preparation of a unique new class of STING agonists: isonucleotidic cyclic dinucleotides and the synthesis of their prodrugs. The presented CDNs stimulate STING with comparable efficiency to ADU-S100, whereas their prodrugs demonstrate activity up to four orders of magnitude better due to the improved cellular uptake. The compounds are very potent inducers of inflammatory cytokines by peripheral blood mononuclear cells (PBMCs). We also report the X-ray crystal structure of the lead inhibitor bound to the wild-type (WT) STING.
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Nucleotídeos Cíclicos , Pró-Fármacos , Citosol/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/química , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/farmacologiaRESUMO
In a series of three studies, we examined whether third-party observers can detect attraction in others based on subtle nonverbal cues. We employed video segments of dates collected from a speed-dating experiment, in which daters went on a brief (approx. 4 min) blind-date and indicated whether they would like to go on another date with their brief interaction partner or not. We asked participants to view these stimuli and indicate whether or not each couple member is attracted to their partner. Our results show that participants could not reliably detect attraction, and this ability was not influenced by the age of the observer, video segment location (beginning or middle of the date), video duration, or general emotion recognition capacity. Contrary to previous research findings, our findings suggest that third-party observers cannot reliably detect attraction in others. However, there was one exception: Recognition rose above chance level when the daters were both interested in their partners compared to when they were not interested. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-02927-0.
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Conventional Nuclear Magnetic Resonance (NMR) analysis relies on H-H/C-H interactions. However, these interactions are sometimes insufficient for an accurate and precise NMR analysis. In this study, we show that 31P NMR parameters can provide critical structural insights into the stereochemistry of phosphorus-containing compounds. For this purpose, we prepared a set of model phosphorus-based proline derivatives, separated diastereoisomers, and determined their absolute configuration by single-crystal X-ray diffraction. After supplementing these results by electronic circular dichroism (ECD) spectroscopy, we combined experimental data and DFT calculations from our model compounds to perform a detailed conformational analysis, thereby determining their relative configuration. Overall, our findings establish an experimental paradigm for combining 31P NMR spectroscopy with other optical methods to facilitate the stereochemical analysis of phosphorus-containing compounds.
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Fósforo , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Conformação Molecular , EstereoisomerismoRESUMO
Preexisting serum albumin-polymer bioconjugates have been formed either through covalent conjugation or supramolecular interactions. However, the viability of producing a bioconjugate where both covalent conjugation and supramolecular interactions have been adopted is yet to be explored. In this work, the noncovalent interaction of two polymers bearing fatty acid-based end-functionalities were compared and the superior binder was carried forward for testing with serum albumin that possessed a polymer conjugated to its Cys34 residue. The studies demonstrated that an albumin-polymer bioconjugate equipped with polymers via both covalent and supramolecular interactions can be successfully achieved.
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Polímeros , Albumina Sérica , Estrutura Molecular , Polímeros/químicaRESUMO
Amine-containing drugs often show poor pharmacological properties, but these disadvantages can be overcome by using a prodrug approach involving self-immolative linkers. Accordingly, we designed l-lactate linkers as ideal candidates for amine delivery. Furthermore, we designed linkers bearing two different cargos (aniline and phenol) for preferential amine cargo release within 15 min. Since the linkers carrying secondary amine cargo showed high stability at physiological pH, we used our strategy to prepare phosphate-based prodrugs of the antibiotic Ciprofloxacin. Therefore, our study will facilitate the rational design of new and more effective drug delivery systems for amine-containing drugs.
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Aminas/química , Preparações Farmacêuticas/química , Fosfatos/química , Pró-Fármacos/química , Antibacterianos/química , Ciprofloxacina/química , Sistemas de Liberação de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Ácido Láctico/químicaRESUMO
Invited for the cover of this issue are Eliska Procházková, Ondrej Baszczynski, and colleagues at IOCB (Prague) and Charles University (Prague). The image depicts phosphorus-based, double-cargo, self-immolative linkers capable of releasing both cargos sequentially after activation by light. Read the full text of the article at 10.1002/chem.202101805.
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Fosfatos , HumanosRESUMO
Unconjugated bilirubin (UCB) is the end-product of heme catabolism in the intravascular compartment. Although beneficial for human health when mildly elevated in the body, when present at greater than a critical threshold concentration, UCB exerts toxic effects that are related to its physico-chemical properties, particularly affecting the central nervous system. The aim of the present study was to characterize bilirubin-10-sulfonate (ranarubin), a naturally occurring bile pigment, including determination of its mixed acidity constants (pKa*). Thanks to the presence of the sulfonic acid moiety, this compound is more polar compared to UCB, which might theoretically solve the problem with an accurate determination of the UCB pKa* values of its propionic acid carboxylic groups. Bilirubin-10-sulfonate was synthesized by modification of a previously described procedure; and its properties were studied by mass spectrometry (MS), nuclear magnetic resonance (NMR), infrared (IR), and circular dichroism (CD) spectroscopy. Determination of pKa* values of bilirubin-10-sulfonate and UCB was performed by capillary electrophoresis with low pigment concentrations in polar buffers. The identity of the synthesized bilirubin-10-sulfonate was confirmed by MS, and the pigment was further characterized by NMR, IR, and CD spectroscopy. The pKa values of carboxylic acid moieties of bilirubin-10-sulfonate were determined to be 5.02, whereas those of UCB were determined to be 9.01. The physico-chemical properties of bilirubin-10-sulfonate were partially characterized with low pKa* values compared to those of UCB, indicating that bilirubin-10-sulfonate cannot be used as a surrogate pigment for UCB chemical studies. In addition, using a different methodological approach, the pKa* values of UCB were found to be in a mildly alkaline region, confirming the conclusions of a recent critical re-evaluation of this specific issue.
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Phosphorus-based self-immolative (SI) linkers offer a wide range of applications, such as smart materials and drug-delivery systems. Phosphorus SI linkers are ideal candidates for double-cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1â day to 2â hours or 5â minutes, as shown for linkers containing p-fluoro phenol. In turn, double cargo linkers bearing p-methyl phenol released their cargo more slowly (4â days, 4â hours, and 15â minutes) than their p-fluoro analogues. The α-hydroxyisobutyrate linker released both cargos in 25â minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms.
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Sistemas de Liberação de Medicamentos , FosfatosRESUMO
Albumin has consistently demonstrated its potential for enhancing the delivery of drugs and polymer-drug conjugates, binding via supramolecular forces within its multiple binding sites. Herein, we introduce saturation transfer difference (STD-NMR) as a method to identify the interactions between a polymer library and bovine serum albumin (BSA). With STD-NMR, the binding ability of polymers can be quickly screened by focusing on their individual structural features, making this technique more suitable for high throughput screening in comparison to traditional fluorescence studies.
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Polímeros , Soroalbumina Bovina , Sítios de Ligação , Espectroscopia de Ressonância Magnética/métodos , Polímeros/metabolismo , Ligação Proteica , Soroalbumina Bovina/químicaRESUMO
Self-immolation (SI) is the key principle of ProTide nucleotide prodrugs such as remdesivir, which is currently used to treat COVID-19 patients. Developing novel tailor-made SI systems requires new analytical methods for the detection and monitoring of SI. We developed a robust method for SI analysis using novel phosphate-based SI linkers with NMR traceable cyclic intermediates to distinguish SI from alternative fragmentation pathways and to monitor cargo release in real time.
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Naphthoquinones isolated from Quambalaria cyanescens (quambalarines) are natural pigments possessing significant cytotoxic and antimicrobial properties. Determining the structure of naphthoquinone compounds is important for the understanding of their biological activities and the informed synthesis of related analogues. Identifying quambalarines is challenging, because they contain a hydroxylated naphthoquinone scaffold and have limited solubility. Here, we report a detailed structural study of quambalarine derivatives, which form strong intramolecular hydrogen bonds (IMHBs) that enable the formation of several tautomers; these tautomers may complicate structural investigation due to their fast interconversion. To investigate tautomeric equilibria and identify new quambalarines, we complemented the experimental NMR spectroscopy data with density functional theory (DFT) calculations.
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Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Basidiomycota/química , Naftoquinonas/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Ligação de Hidrogênio , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/isolamento & purificaçãoRESUMO
Bis(benzothienyl)ethene sulfones are very interesting molecules for super-resolution microscopy due to their photoswitching properties. However, functionalization of the 'classical' bis(benzothienyl)ethene sulfones with a five-membered central ring leads to significant decrease of quantum yields of photoconversion of the fluorescent closed form of the dye to the non-fluorescent open form that limits their application in microscopy. Here, we designed and synthesized diarylethenes with a fluorinated four-membered central ring that adds extra strain to the closed form of the dye. The reaction mechanism of their formation was studied, and byproducts formed upon structural rearrangement of the benzothiophene fragment were characterized. The photochromic properties of the new molecules were investigated by NMR and absorption spectroscopy. Some of these compounds show enhanced tendency to ring opening and have quantum yields of the ring-opening reaction in the range of 0.2-0.5.
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Photochromic systems with an ultrahigh rate of thermal relaxation are highly desirable for the development of new efficient photochromic oscillators. Based on DFT calculations, we designed a series of 5-phenylazopyrimidines with strong push-pull character in silico and observed very low energy barriers for the thermal (Z)-to-(E) isomerization. The structure of the (Z)-isomer of the slowest isomerizing derivative in the series was confirmed by NMR analysis with in situ irradiation at low temperature. The substituents can tune the lifetime of thermal back isomerization from hundreds of microseconds to several nanoseconds (8 orders of magnitude). The photoswitching parameters were extracted from transient absorption techniques and a dominant rotation mechanism of the (Z)-to-(E) thermal fading was proposed based on DFT calculations.
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Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC), the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.
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Inibidores Enzimáticos/química , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Exossomos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Piridazinas/química , Piridazinas/metabolismo , Piridazinas/uso terapêutico , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielina Fosfodiesterase/farmacologia , Relação Estrutura-AtividadeRESUMO
We report on the discovery of norbornyl moiety as a novel structural motif for cyclin-dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics-based scoring was used to rationalize the affinities. In conclusion, the discovered 9-hydroxymethylnorbornyl moiety was shown by joint experimental-theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.
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Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Norbornanos/farmacologia , Nucleosídeos/análogos & derivados , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
Humans and great apes are highly social species, and encounter conspecifics throughout their daily lives. During social interactions, they exchange information about their emotional states via expressions through different modalities including the face, body and voice. In this regard, their capacity to express emotions, intentionally or unintentionally, is crucial for them to successfully navigate their social worlds and to bond with group members. Darwin (1872) stressed similarities in how humans and other animals express their emotions, particularly with the great apes. Here, we show that emotional expressions have many conserved, yet also a number of divergent features. Some theorists consider emotional expressions as direct expressions of internal states, implying that they are involuntary, cannot be controlled and are inherently honest. Others see them as more intentional and/ or as indicators of the actor's future behavior. After reviewing the human and ape literature, we establish an integrative, evolutionary perspective and provide evidence showing that these different viewpoints are not mutually exclusive. Recent insights indicate that, in both apes and humans, some emotional expressions can be controlled or regulated voluntarily, including in the presence of audiences, suggesting modulation by cognitive processes. However, even non-intentional expressions such as pupil dilation can nevertheless inform others and influence future behavior. In sum, while showing deep evolutionary homologies across closely related species, emotional expressions show relevant species variation.