Synthesis, kinetic studies, and QSAR of dinucleoside polyphosphate derivatives as human AK1 inhibitors.

Adenylate kinase (AK) plays a crucial role in the metabolic monitoring of cellular adenine nucleotide homeostasis by catalyzing the reversible transfer of a phosphate group between ATP and AMP, yielding two ADP molecules. By regulating the nucleotide levels and energy metabolism, the enzyme is considered a disease modifier and potential therapeutic target for various human diseases, including malignancies and inflammatory and neurodegenerative disorders. However, lacking approved drugs targeting AK hinders broad studies on this enzyme's pathological importance and therapeutic potential. In this work, we determined the effect of a series of dinucleoside polyphosphate derivatives, commercially available (11 compounds) and newly synthesized (8 compounds), on the catalytic activity of human adenylate kinase isoenzyme 1 (hAK1). The tested compounds belonged to the following groups: (1) diadenosine polyphosphates with different phosphate chain lengths, (2) base-modified derivatives, and (3) phosphate-modified derivatives. We found that all the investigated compounds inhibited the catalytic activity of hAK1, yet with different efficiencies. Three dinucleoside polyphosphates showed IC50 values below 1 µM, and the most significant inhibitory effect was observed for P1-(5'-adenosyl) P5-(5'-adenosyl) pentaphosphate (Ap5A). To understand the observed differences in the inhibition efficiency of the tested dinucleoside polyphosphates, the molecular docking of these compounds to hAK1 was performed. Finally, we conducted a quantitative structure-activity relationship (QSAR) analysis to establish a computational prediction model for hAK1 modulators. Two PLS-regression-based models were built using kinetic data obtained from the AK1 activity analysis performed in both directions of the enzymatic reaction. Model 1 (AMP and ATP synthesis) had a good prediction power (R2 = 0.931, Q2 = 0.854, and MAE = 0.286), while Model 2 (ADP synthesis) exhibited a moderate quality (R2 = 0.913, Q2 = 0.848, and MAE = 0.370). These studies can help better understand the interactions between dinucleoside polyphosphates and adenylate kinase to attain more effective and selective inhibitors in the future.

Fluorescent properties in solid-state and solution of novel tricyclic derivatives of chloro/bromophenylchromanones and 2-methylpyrazoline.

In this work, we reported the synthesis and spectroscopic characterization of seven novel tricyclic compounds resulting from the reaction of 3-benzylidenechromanone with Cl or Br substituent in different positions and without halogen with methylhydrazine. The structural characterization of compounds was done through different techniques i.e., FTIR,1HNMR,a single and powder X-Ray diffraction. Moreover, fluorescence quantum yield and lifetime assessed their fluorescent properties in the solid state and various solvents. Derivatives with Cl or Br substituent in positions 2 and 4 are isostructural. 4-Cl, 4-Br and 3-Cl compounds exhibit fluorescence with moderate efficiency (quantum yield 0.11-0.26) in solid state due to specific arrangements, so-called π-stack brick stone with head-to-tail self-assembly. Other crystalline compounds (2-Cl, 2-Br and 3-Br) that exhibit negligible fluorescence quantum yield have crossed V-type arrangement. In the solution, the nonhalogenated compound shows the best fluorescence efficiency. In turn, the presence of halogen atoms results in fluorescence decreasing. TD-DFT study revealed that unsubstituted compound higher emissive in solution has a different electron density distribution at HOMO and LUMO levels than less emissive substituted compounds (A3 and A3).

Systematic Study of Solid-State Fluorescence and Molecular Packing of Methoxy-trans-Stilbene Derivatives, Exploration of Weak Intermolecular Interactions Based on Hirshfeld Surface Analysis.

In recent years, fluorescent compounds that emit efficiently in the solid state have become particularly interesting, especially those that are easily prepared and inexpensive. Hence, exploring the photophysical properties of stilbene derivatives, supported by a detailed analysis of molecular packing obtained from single-crystal X-ray diffraction data, is a relevant area of research. A complete understanding of the interactions to determine the molecular packing in the crystal lattice and their effect on the material's physicochemical properties is essential to tune various properties effectively. In the present study, we examined a series of methoxy-trans-stilbene analogs with substitution pattern-dependent fluorescence lifetimes between 0.82 and 3.46 ns and a moderate-to-high fluorescence quantum yield of 0.07-0.69. The relationships between the solid-state fluorescence properties and the structure of studied compounds based on X-ray analysis were investigated. As a result, the QSPR model was developed using PLSR (Partial Least Squares Regression). Decomposition of the Hirshfeld surfaces (calculated based on the arrangement of molecules in the crystal lattice) revealed the various types of weak intermolecular interactions that occurred in the crystal lattice. The obtained data, in combination with global reactivity descriptors calculated using HOMO and LUMO energy values, were used as explanatory variables. The developed model was characterized by good validation metrics (RMSECAL = 0.017, RMSECV = 0.029, R2CAL = 0.989, and R2CV = 0.968) and indicated that the solid-state fluorescence quantum yield of methoxy-trans-stilbene derivatives was mainly dependent on weak intermolecular C…C contacts corresponding to π-π stacking and C…O/O…C interactions. To a lesser extent and inversely proportional, the fluorescence quantum yield was affected by the interactions of the type O…H/H…O and H…H and the electrophilicity of the molecule.

Leukocyte deep learning classification assessment using Shapley additive explanations algorithm.

INTRODUCTION: A peripheral blood smear is a basic test for hematological disease diagnosis. This test is performed manually in many places worldwide, which requires both time and qualified staff. Large laboratories are equipped with digital morphology analyzers, some of which are based on deep learning methods. However, it is difficult to explain to scientists how they work. In this paper, we proposed to add an explanatory factor to enhance the interpretability of deep learning models in leukocyte classification. METHODS: 10 297 single images of leukocytes obtained from peripheral blood smears were included in this study. Pre-trained and fully trained VGG16 and VGG19 models were used to classify the leukocytes, and Shapley Additive Explanations (SHAP) DeepExplainer was applied to visualize the area of cells that were significant for classification. The output images from the DeepExplainer were compared with cellular elements that are essential to laboratory practice. RESULTS: The accuracy of our fully trained models was 99.81% for VGG16 and 99.79% for VGG19. It achieved slightly better results than the partially trained model, which scored 98.67% for VGG16 and 98.33% for VGG19. Their SHAP explanations indicated the significance of cellular structures in microscopic examination. Explanations in the pre-trained models have proved the cell and nucleus contours to be relevant to classification, while explanations in the fully trained models pointed to the cytoplasm area. CONCLUSION: Despite different SHAP DeepExplainer explanations for fully and partially trained models, this method appears to be helpful for the verification of leukocyte classification in automated peripheral blood smear examination.

Comparative study of titanium dioxide to improve the quality of finished cosmetic products.

OBJECTIVE: Titanium dioxide (TiO2 ) pigments (pure) or with a hydrophobic coating of triethoxycaprylylsilane (TECSi) used in cosmetics. Using different methods, we studied properties of commercially available pure and coated pigment. We determined the elemental composition of pigments that differ in their behaviour in a cosmetic formulation. The significant differences in the coating composition were revealed. METHODS: UV-Vis absorption spectroscopy allowed us to investigate the pigment purity and determined the polymorph form in pigments. FTIR was employed to identify functional groups present in the samples with the modified surface. XRD, DLS, TEM and DCS were applied to characterize particle size and morphology. The experiment of ED-XRF method was used to determine the elemental composition of pigments that differ in their behaviour in a cosmetic formulation. RESULTS: UV-Vis spectroscopy was used to detect organic pollutants in particular batches, which were not detected in the cases of the tested samples. Solid UV-Vis spectroscopy and XRD revealed which crystalline form of TiO2 is present in pigments. TEM and DLS methods were used to characterize particle size and morphology as well as DCS method, which provide more accurate information about form (separated or clustered particles) of pigments' particles in suspensions. Based on FTIR spectra, the presence of a coating in the raw material was identified, and the tell-tale signal of the silane group. On the contrary, spectroscopy of washed-out product can identify the well or poorly modified pigment. Applying ED-XRF, it turned out that the content of silicon (and consequently of the TECSi) was lower than that declared by the manufacturer. CONCLUSION: Our data indicate how we can recognize poorly coated pigments in raw material. The results show that ED-XRF method is nondestructive, effective and fast, hence, can be successfully introduced into preproduction pigment control in cosmetic industry.

OBJECTIF: Les pigments de dioxyde de titane (TiO2 ) (pur) ou avec un revêtement hydrophobe de triéthoxycaprylylsilane (TECSi) sont utilisés dans les cosmétiques. En utilisant différentes méthodes, nous avons étudié les propriétés des pigments purs et enrobés disponibles dans le commerce. Nous avons déterminé la composition élémentaire des pigments qui diffèrent dans leur comportement dans une formulation cosmétique. Les différences significatives dans la composition de l'enrobage ont été révélées. METHODES: La spectroscopie d'absorption UV-Vis nous a permis d'étudier la pureté des pigments et de déterminer la forme polymorphe des pigments. L'IRTF a été utilisé pour identifier les groupes fonctionnels présents dans les échantillons à la surface modifiée. XRD, DLS, TEM et DCS ont été appliqués pour caractériser la taille et la morphologie des particules. L'expérience de la méthode ED-XRF a été utilisée pour déterminer la composition élémentaire des pigments qui diffèrent dans leur comportement dans une formulation cosmétique. RÉSULTATS: La spectroscopie UV-Vis a été utilisée pour détecter des polluants organiques dans des lots particuliers, qui n'ont pas été détectés dans les cas des échantillons testés. La spectroscopie UV-Vis et la XRD ont révélé quelle forme cristalline de TiO2 est présente dans les pigments. Les méthodes TEM et DLS ont été utilisées pour caractériser la taille et la morphologie des particules ainsi que la méthode DCS qui fournit des informations plus précises sur la forme (particules séparées ou agglomérées) des particules de pigments dans les suspensions. Sur la base des spectres FTIR, la présence d'un revêtement dans la matière première a été identifiée, ainsi que le signal révélateur du groupe silane. D'autre part, la spectroscopie du produit délavé permet d'identifier le pigment bien ou mal modifié. En appliquant l'ED-XRF, il s'est avéré que la teneur en silicium (et par conséquent du TECSi) était inférieure à celle déclarée par le fabricant. CONCLUSION: Nos données indiquent comment nous pouvons reconnaître les pigments mal enrobés dans la matière première. Les résultats montrent que la méthode ED-XRF est non-destructive, efficace et rapide, et qu'elle peut donc être introduite avec succès dans le contrôle des pigments en pré-production dans l'industrie cosmétique.

Analysis of White Mulberry Leaves and Dietary Supplements, ATR-FTIR Combined with Chemometrics for the Rapid Determination of 1-Deoxynojirimycin.

Diabetes mellitus is a metabolic disease affecting more people every year. The treatment of diabetes and its complications involve substantial healthcare expenditures. Thus, there is a need to identify natural products that can be used as nutraceuticals to prevent and treat early-stage diabetes. White mulberry (Morus alba L.) is a plant that has been used in traditional Chinese medicine for thousands of years due to its many beneficial biological properties. White mulberry leaves are a source of 1-deoxynojirimycin (DNJ), which, due to its ability to inhibit α-glucosidase, can be used to regulate postprandial glucose concentration. In addition to consuming dried white mulberry leaves as herbal tea, many functional foods also contain this raw material. The development of the dietary supplements market brings many scientific and regulatory challenges to the safety, quality and effectiveness of such products containing concentrated amounts of nutraceuticals. In the present study, the quality of 19 products was assessed by determining the content of DNJ, selected (poly)phenols and antioxidant activity (DPPH• assay). Nine of these products were herbal teas, and the other samples were dietary supplements. These results indicate the low quality of tested dietary supplements, the use of which (due to the low content of nutraceuticals) cannot bring the expected beneficial effects on health. Moreover, a method for determining the content of DNJ (the essential component for antidiabetic activity) based on ATR-FTIR spectroscopy combined with PLS regression has been proposed. This might be an alternative method to the commonly used chromatographic process requiring extraction and derivatization of the sample. It allows for a quick screening assessment of the quality of products containing white mulberry leaves.

HATS5m as an Example of GETAWAY Molecular Descriptor in Assessing the Similarity/Diversity of the Structural Features of 4-Thiazolidinone.

Among the various methods for drug design, the approach using molecular descriptors for quantitative structure-activity relationships (QSAR) bears promise for the prediction of innovative molecular structures with bespoke pharmacological activity. Despite the growing number of successful potential applications, the QSAR models often remain hard to interpret. The difficulty arises from the use of advanced chemometric or machine learning methods on the one hand, and the complexity of molecular descriptors on the other hand. Thus, there is a need to interpret molecular descriptors for identifying the features of molecules crucial for desirable activity. For example, the development of structure-activity modeling of different molecule endpoints confirmed the usefulness of H-GETAWAY (H-GEometry, Topology, and Atom-Weights AssemblY) descriptors in molecular sciences. However, compared with other 3D molecular descriptors, H-GETAWAY interpretation is much more complicated. The present study provides insights into the interpretation of the HATS5m descriptor (H-GETAWAY) concerning the molecular structures of the 4-thiazolidinone derivatives with antitrypanosomal activity. According to the published study, an increase in antitrypanosomal activity is associated with both a decrease and an increase in HATS5m (leverage-weighted autocorrelation with lag 5, weighted by atomic masses) values. The substructure-based method explored how the changes in molecular features affect the HATS5m value. Based on this approach, we proposed substituents that translate into low and high HATS5m. The detailed interpretation of H-GETAWAY descriptors requires the consideration of three elements: weighting scheme, leverages, and the Dirac delta function. Particular attention should be paid to the impact of chemical compounds' size and shape and the leverage values of individual atoms.

Investigating the Potential Use of Chemical Biopsy Devices to Characterize Brain Tumor Lipidomes.

The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method of enabling the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.

Discrimination of Adulterated Ginkgo Biloba Products Based on 2T2D Correlation Spectroscopy in UV-Vis Range.

Ginkgo biloba is a popular medicinal plant widely used in numerous herbal products, including food supplements. Due to its popularity and growing economic value, G. biloba leaf extract has become the target of economically motivated adulterations. There are many reports about the poor quality of ginkgo products and their adulteration, mainly by adding flavonols, flavonol glycosides, or extracts from other plants. In this work, we developed an approach using two-trace two-dimensional correlation spectroscopy (2T2D COS) in UV-Vis range combined with multilinear principal component analysis (MPCA) to detect potential adulteration of twenty G. biloba food supplements. UV-Vis spectral data are obtained for 80% methanol and aqueous extracts in the range of 245-410 nm. Three series of two-dimensional correlation spectra were interpreted by visual inspection and using MPCA. The proposed relatively quick and straightforward approach successfully differentiated supplements adulterated with rutin or those lacking ginkgo leaf extract. Supporting information about adulteration was obtained from the difference between the DPPH radical scavenging capacity of both extracts and from chromatographic (HPLC-DAD) fingerprints of methanolic samples.

Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies.

Rapid and Accurate Approach for Honeybee Pollen Analysis Using ED-XRF and FTIR Spectroscopy.

Since honeybee pollen is considered a "perfectly complete food" and is characterized by many beneficial properties (anti-inflammatory, antioxidant, anti-bacterial, etc.), it has begun to be used for therapeutic purposes. Consequently, there is a high need to develop methods for controlling its composition. A thorough bee pollen analysis can be very informative regarding its safety for consumption, the variability of its composition, its biogeographical origin, or harvest date. Therefore, in this study, two reliable and non-destructive spectroscopy methods, i.e., ED-XRF and ATR-FTIR, are proposed as a fast approach to characterize bee pollen. The collected samples were derived from apiaries located in west-central Poland. Additionally, some commercially available samples were analyzed. The applied methodology was optimized and combined with sophisticated chemometric tools. Data derived from IR analyses were also subjected to two-dimensional correlation spectroscopy. The developed ED-XRF method allowed the reliable quantification of eight macro- and micro-nutrients, while organic components were characterized by IR spectroscopy. Principal component analysis, cluster analysis, and obtained synchronous and asynchronous maps allowed the study of component changes occurring dependently on the date and location of harvest. The proposed approach proved to be an excellent tool to monitor the variability of the inorganic and organic content of bee pollen.

Solid phase microextraction chemical biopsy tool for monitoring of doxorubicin residue during in vivo lung chemo-perfusion.

Development of a novel in vivo lung perfusion (IVLP) procedure allows localized delivery of high-dose doxorubicin (DOX) for targeting residual micrometastatic disease in the lungs. However, DOX delivery via IVLP requires careful monitoring of drug level to ensure tissue concentrations of this agent remain in the therapeutic window. A small dimension nitinol wire coated with a sorbent of biocompatible morphology (Bio-SPME) has been clinically evaluated for in vivo lung tissue extraction and determination of DOX and its key metabolites. The in vivo Bio-SPME-IVLP experiments were performed on pig model over various (150 and 225 mg/m2) drug doses, and during human clinical trial. Two patients with metastatic osteosarcoma were treated with a single 5 and 7 µg/mL (respectively) dose of DOX during a 3-h IVLP. In both pig and human cases, DOX tissue levels presented similar trends during IVLP. Human lung tissue concentrations of drug ranged between 15 and 293 µg/g over the course of the IVLP procedure. In addition to DOX levels, Bio-SPME followed by liquid chromatography-mass spectrometry analysis generated 64 metabolic features during endogenous metabolite screening, providing information about lung status during drug administration. Real-time monitoring of DOX levels in the lungs can be performed effectively throughout the IVLP procedure by in vivo Bio-SPME chemical biopsy approach. Bio-SPME also extracted various endogenous molecules, thus providing a real-time snapshot of the physiology of the cells, which might assist in the tailoring of personalized treatment strategy.

Comparison of Metabolomic Profiles of Organs in Mice of Different Strains Based on SPME-LC-HRMS.

Given that the extent to which genetics alters the metabolomic profile of tissues is still poorly understood, the current study aimed to characterize and investigate the metabolite profiles of brain, liver, kidney and skeletal muscle of two common mouse inbred strains (BALB/c, C57BL/6) and one outbred stock (CD1) for strain-specific differences. Male mice (n = 15) at the age of 12 weeks were used: BALB/c (n = 5), C57BL/6 (n = 5) and CD1 (n = 5). Solid phase microextraction (SPME) was applied for the extraction of analytes from the tissues. SPME fibers (approximately 0.2 mm in diameter) coated with a biocompatible sorbent (4 mm length of hydrophilic-lipophilic balanced particles) were inserted into each organ immediately after euthanasia. Samples were analyzed using liquid chromatography coupled to a Q-Exactive Focus Orbitrap mass spectrometer. Distinct interstrain differences in the metabolomic patterns of brain and liver tissue were revealed. The metabolome of kidney and muscle tissue in BALB/c mice differed greatly from C57BL/6 and CD1 strains. The main compounds differentiating all the targeted organs were alpha-amino acids, purine nucleotides and fatty acid esters. The results of the study indicate that the baseline metabolome of organs, as well as different metabolic pathways, vary widely among general-purpose models of laboratory mice commonly used in biomedical research.

Interactions in flavanone and chalcone derivatives: Hirshfeld surface analysis, energy frameworks and global reactivity descriptors.

The present study examines a series of flavanone and chalcone derivatives substituted with electron-withdrawing groups (Cl or Br) and electron-donating groups (OH, CH3 and OCH3), namely, 7-methoxy-2-phenyl-3,4-dihydro-2H-1-benzopyran-4-one, C16H14O3, 2-(4-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one, C16H14O3, 2-(4-methoxyphenyl)-6-methyl-3,4-dihydro-2H-1-benzopyran-4-one, C17H16O3, 2-(4-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-one, C15H11ClO2, 8-bromo-6-methyl-2-phenyl-3,4-dihydro-2H-1-benzopyran-4-one, C16H13BrO2, (2E)-1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one, C16H14O3, and (2E)-1-(2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, C15H12O3. It compares the two groups of derivatives with regard to their intermolecular interactions in the crystal lattice and lattice energy calculations, together with energy framework visualization and global reactivity descriptors (chemical hardness, chemical potential and electrophilicity index). It also discusses the relationships between different noncovalent interactions derived from Hirshfeld surface analysis, crystal lattice energy and global reactivity descriptors of the compounds.

Detection of adulterants in dietary supplements with Ginkgo biloba extract by attenuated total reflectance Fourier transform infrared spectroscopy and multivariate methods PLS-DA and PCA.

The infrared spectroscopy with attenuated total reflectance (ATR) sampling coupled with chemometric methods has been applied to non-destructive detection of adulterants in dietary supplements containing Ginkgo biloba extract. The sample set comprised the spectra of six drugs and sixteen dietary supplements with ginkgo leaf extract. Spectral data (900-1800 cm-1) were analyzed using multivariate partial least squares regression combined with a discriminant analysis (PLS-DA). The second derivative of spectra followed by mean centering was used as pre-processing method. Three models were constructed and validated for detection of potential adulterants: kaempferol, quercetin, and rutin. The iPLS-DA classification models achieved about 87.5%, 93,7%, and 87,5% of correct classification for adulteration with kaempferol, quercetin and rutin, respectively. The results obtained from classification models were verified by chromatographic fingerprints of unhydrolyzed sample extracts. Two-trace two-dimensional asynchronous correlation maps were constructed from pairs of spectra (each dietary supplement spectrum vs. averaged spectrum of drugs) and then analyzed by multiway PCA which revealed good discrimination between samples.

An application of QSRR approach and multiple linear regression method for lipophilicity assessment of flavonoids.

The analysis of quantitative structure-retention relationships (QSRR) is useful tool for assessment of compound's lipophilicity/hydrophobicity due to similarity between its retention in chromatographic system and ability to permeation through biological membranes. The main goal of this study was to compare usefulness of two reversed-phase chromatographic columns (Synergy POLAR and Synergy-FUSION) for lipophilicity assessment of 30 structurally diverse flavonoids using the QSRR approach and multiple linear regression method. The developed MLR models included the mechanistically interpretable geometrical descriptors: 3D Molecule Representation of Structure based on Electron diffraction (3D-MoRSE) and Radial Distribution Function (RDF). Both models were evaluated by the internal and external validation and selected descriptors were further interpreted. According to obtained results the FUSION-RP column can be recommended to log kw prediction of flavonoids. The comprehensive interpretation of molecular descriptors was used to present the molecular mechanisms and structural features governing the chromatographic retention of tested compounds.

Quantitative relationships between structure and cytotoxic activity of flavonoid derivatives. An application of Hirshfeld surface derived descriptors.

Quantitative relationships between the structure and cytotoxic activity of series flavonoid derivatives were examined. The first regression-based model, developed for 18 flavanone-2-pyrazoline hybrids, involved two interpretable descriptors: a Mor04v and partial atomic charge. The second model, developed for structurally diverse set of compounds, was based on descriptors derived from Hirshfeld surface analysis. This model suggests that cytotoxic activity of compounds can be successfully predicted based on a fraction of H⋯H contacts and a fraction of interactions involving a halogen atom. For non-halogen derivatives, the data reveal that cytotoxic activity is inversely proportional to the percentage of O⋯H and N⋯H close contacts to Hirshfeld surface, while directly proportional to the percentage of H⋯H interactions. Chlorine (1k) and bromine (1l) derivatives of compounds, containing flavanone fused with N-methyl-2-pyrazoline, exhibited high cytotoxic potential against HL-60 cancer cell line (IC50<10µM). The cytotoxicity of 1k and 1l towards normal cells (HUVEC) was 10 and 25-fold lower, respectively.

The synthesis, lipophilicity and cytotoxic effects of new ruthenium(II) arene complexes with chromone derivatives.

A series of arene ruthenium(II) complexes with the general formula [(η(6)-arene)Ru(L)X2] (where arene=p-cymene, benzene, hexamethylbenzene or mesitylene, L=aminoflavone or aminochromone derivatives and X=Cl, I) were synthesized and characterized by elemental analysis, MS, IR and (1)H NMR spectroscopy. The stability of the selected complexes was assessed by UV-Vis spectroscopy in 24-hour period. The lipophilicity of the synthesized complexes was determined by the shake-flask method, and their cytotoxicity evaluated in vitro on patient-derived melanoma populations. The most active complexes against melanoma cells contain 7-aminoflavone and 6-aminoflavone as a ligand. The relationship between the cytotoxicity of all the obtained compounds and their logP values was determined and briefly analyzed with two different patterns observed.

Development and optimization of the activated charcoal suspension composition based on a mixture design approach.

In this study, a new drug product containing activated charcoal was designed and developed. The excipient levels in the pharmaceutical formulation were optimized using a mixture design approach. The adsorption power of the activated charcoal suspension was selected as the critical quality attribute influencing the efficacy of medical treatment. Significant prognostic models (p<0.05) were obtained to describe in detail the interrelations between excipient levels and the adsorption power of the formulation. Liquid flavour had a critical impact on the adsorption power of the suspension. Formulations containing the largest amount of liquid flavour showed the lowest adsorption power. Sorbitol was not adsorbed onto activated charcoal so strongly as liquid flavour. A slight increase in the content of carboxymethylcellulose sodium led to a marked decrease in adsorption power. The obtained mathematical models and response surface allowed selection of the optimal composition of excipients in a final drug product.