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Exploring the redox mechanism of 9-acridinyl amino acid derivatives by electrochemical and theoretical approach
No full textInvestigating and understanding the redox characteristics of potential anticancer agents is of great importance, as these properties are the key factor in the anticancer potential of drugs and can impact the mechanism of action, stability, metabolism, and selectivity of the drug toward cancer cells. Four compounds, previously confirmed to possess notable in vitro anticancer activity and the ability to interact with DNA, were subjected to a detailed electrochemical study. These are 9-acridinyl amino acid derivatives (9R-A), which were investigated in this study using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) with a glassy carbon electrode. The effects of pH (ranging from pH 2–9) and scan rate were thoroughly examined. The findings revealed that three independent oxidation and reduction processes occurred, all of which were diffusion-controlled. Two electroactive regions of the molecule contribute to these redox processes: the nitrogen (N10) of the acridine ring and the enamine nitrogen (N11) in the derivative's side chain. In 9R-A, the acridine ring undergoes a two-electron oxidation: first forming a monomeric radical cation that dimerizes, then undergoing a second electron transfer to yield a new radical cation. The reduction mechanism similarly involves a two-electron transfer, producing a monomeric radical that dimerizes and later forms a new radical. A significant factor in the redox behavior of 9-acridinyl amino acid derivatives is the presence of a secondary amine in the side-chain substituent. This amine undergoes oxidation via the loss of a single electron, resulting in the formation of a monomeric radical cation that is stabilized through deprotonation. While the oxidation mechanism appears to be consistent across all four 9R-A derivatives, differences in their oxidation affinity arise due to structural variations in the side-chain substituents. The experimental electrochemical findings were further supported by computational chemistry. Quantum chemical parameter evaluations provide deeper insights into the oxidation and reduction mechanisms, particularly in relation to the influence of substituents on these processes
Утицај сушења, замрзавања и поновног овлаживања на филтрат земљишта у киселим и калцитним земљиштима
No full textThis study investigates the impact of drying-rewetting and freezingrewetting events on soil leachate ion composition across two contrasting geochemical settings through a series of controlled laboratory experiments. Dissolution of ions (Na⁺, K⁺, Ca²⁺, Mg²⁺, Al³⁺, Fe³⁺, Mn²⁺, F⁻, Cl⁻, NO₂⁻, SO₄²⁻, NO₃⁻, PO₄³⁻) in soil leachate was analyzed following rewetting cycles after drying and freezing treatments. Results indicate that variations in leachate ion concentrations are primarily influenced by bedrock type, while drying-rewetting and freezing-rewetting treatments did not significantly impact overall variance. However, some inconsistent differences were observed: higher K⁺ concentrations in calcareous soils and Al³⁺, Fe³⁺ and Mn²⁺ in acidic soils after drying, higher anion concentrations in calcareous soils in both treatment leachates compared to controls. Findings highlight that the effects of drying, freezing, and rewetting are inherently linked to treatment type, ion characteristics, and geochemical conditions
Chaotropic chromatography method for ziprasidone and its five impurities determination, developed by AQbD
No full textObjective:
The main objective of this study was to develop a reliable and robust AQbD complient chaotropic
chromatography method suitable for quality control of ziprasidone (ZPS) and its five impurities in
capsules.
Methods:
The influence of Critical Method Parameters, CMPs (initial and final methanol content in the
mobile phase, gradient duration) on the set of selected Critical Method Attributes, CMAs (retention
time (tr) of imp. V (tr_imp.V), the time that elapsed from the elution of the first to the elution of the
last peak (tr_imp. V - tr_imp. I), separation factor for unknown impurity x and impurity III (S) and
average values of width of peaks according to the USP ()) was studied by Box-Behnken
design (BBD) in Design-Expert® 11.0.0. Monte Carlo simulations were performed in MATLAB®
R2018b software to propagate the errors resulting from the calculation of the model coefficients to the
selected responses and obtain their predictive distribution, which is graphically represented in the form
of the Design Space (DS). The separation was performed on an XTerra C8 (150×4.6 mm, 3.5 μm)
column with gradient elution. The aqueous part of the mobile phase was a 100 mM aqueous solution of
perchloric acid, pH 2.5 adjusted with 10 M sodium hydroxide, while the organic part of the mobile phase
was methanol. During the optimization, initial/final methanol content and gradient duration were
changed according to the experimental plan defined by BBD, while other chromatographic
conditions were kept constant - detection wavelength at 230 nm, mobile phase flow rate 1 mL min–
1, column and autosampler temperature were set on 30ºC and 15ºC, respectively. The injection
volume was fixed at 15 μL.
Results:
The experimental results obtained during the optimization phase were used to create mathematical
models describing the dependence of the CMAs on the CMPs studied. Based on the coefficients of the
mathematical models, it was found that the duration of the gradient had the greatest influence on the
observed responses. Increasing the duration of the gradient increases the values of the CMAs. In
addition, the response values are more sensitive to the change in the final methanol content than to the
change in the initial methanol content. An increase in the initial and final methanol content leads to a
decrease in the values of the CMAs. The DS was calculated based on a probability π ≥ 80% for the
selected CMAs within the predefined acceptance criteria (tr_imp. V < 15.5 min, tr_imp. V – tr_imp. I < 12 min,
S ≥ 0 min and WUSP ≤ 0.235 min) and an working point was selected: initial methanol content 38.5%,
final methanol content 77.5% and gradient duration 16.25 min. The robustness testing of the method
quantitative performances was performed using the Plackett-Burman (PB) design. It was found that Pimp
II and Pimp V were significantly affected by the mobile phase flow rate and gradient duration. Finally, the
method was validated and its reliability for routine quality control in capsules was confirmed.
Conclusions:
A reliable and robust, AQbD compliant chaotropic chromatography method for efficient baseline
separation and accurate determination of ZPS and its five impurities from capsules was developed. The
DS was defined based on a probability π ≥ 80% for the selected CMAs within the predefined acceptance
criteria. A working point, selected from the middle of the computed DS, provided good agreement
between the experimentally obtained and predicted CMAs. It was shown that all the criteria defined by
analytical target profile (ATP) can be achieved in less than 16 minutes
Machine learning in predictive modelling of mixed mode chromatography analysis of small drug molecules
No full textObjective:
When drug analysis is challenged with the mixture of analytes having very different physical -
chemical properties such as polar, non-polar, organic, inorganic, ionized and / or non-ionized
analytes, the combination of several analytical approaches is needed resulting in time and cost
consuming laboratory work. Fortunately, recently developed mixed mode stationary phases in
liquid chromatography may serve as valuable assistance. This refers to the use of stationary phase
in which several separation mechanisms are integrated in the composition of a single
chromatographic column thus enabling the beneficial reduction of the number of required analyses
for one complex sample. For that reason, the popularity of MMC has been growing fast in recent
years. However, in line with this achievement, working in mixed mode chromatography system is
accompanied by large number of intermolecular interactions governing separations being related
both to the properties of the analyte and experimental conditions (instrumental and mobile phase
related) [1]. In order to get insight into relative contribution of aforementioned factors to retention
of selected group of analytes, Mixed Quantitative Structure Retention Relationship (QSRR) study
is a preferred approach. QSSR study implies the regression analysis applied to relate the physicalchemical
properties of analytes reflected by assigned molecular descriptors with their retention
behaviour in predefined experimental space described by the range of chromatographic conditions
[2]. Due to noted complexity of data for building QSSR model, the use of machine learning
algorithms is considered as necessary tool.
Methods:
The QSRR study was performed on 31 pharmaceuticals covering wide range of polarities and acid -
base properties and their divergent retention in bimodal RP/WCX system (Thermo Acclaim Mixed
Mode WCX-1 3 μm, 2.1x150 mm column). This system was subjected to variations of the mobile
phase composition (30-50% (v/v) of acetonitrile; 3.8-5.6 pH value and 20-40 mM ionic strength of
acetic buffer) and column temperature (30–38 °C) according to the plan of face-centred central
composite design of experiments. The machine learning algorithm based on gradient boosted trees
was used for relating these independent variables to retention factors of analytes.
Results:
QSRR models were developed upon the whole data set (global model) and upon discrete parts,
related to similarly ionized analytes (local models). Root mean squared errors of prediction for
global and local models for cations, anions and neutrals were respectively 0.131; 0.105; 0.102 and
0.042 with coefficient of determination 0.947; 0.872; 0.954 and 0.996, indicating satisfactory
performances of all models, with slightly better accuracy of local ones.
Conclusions:
The research showed that influences of experimental parameters were dependant on the molecule’s
ionisation potential. The molecular descriptors highlighted by models pointed out that electrostatic
and hydrophobic interactions and hydrogen bonds participate in the retention process. The
molecule’s conformation significance was evaluated along with the topological relationship
between the interaction centres, explicitly determined for each molecular species through local
models
Innovative approach to the development of separation methods for the drug quality control
No full textObjective:
An innovative development of analytical methods for the drug quality control, also known as
Analytical Quality by Design (AqbD), provides a systematic way of generating knowledge as an
analytical procedure evolves throughout its lifecycle. This implies the application of robust
optimization to define ranges of method parameters whose combination ensures adequate method
performance. Such an approach promotes the efficiency of quality control of medicinal products,
increases the reliability of QC results and promotes the continuous improvement of analytical
procedures.
Methods:
Several tasks must be performed during method development employing AqbD approach: (i)
compiling an analytical target profile (ATP), (ii) performing risk assessments, (iii) identifying the
desirable analytical procedure performans characteristics, over the reportable range, (iv)
identifying the Analytical Procedure Attributes (APAs) that need to be tested, (v) Design of
Experiments (DoE) and modelling to explore likely Analytical Procedure Parameters (APPs)
interactions, compute Design Space (DS) and define an analytical control strategy and (iv) fully
document the procedure.
Results:
The basis of the AQbD concept is the analytical target profile (ATP) that brings a set of criteria
defining what is to be measured, in which concentration range, in which matrix, etc., as well as
requirements for the properties of the method itself named APAs. The next step is to assess the
quality risk by identifying all potential variables that could make the system vulnerable,
categorizing the identified factors and finally prioritizing them according to their severity for the
system. The most critical factors need to be defined as APPs and their impact on the APAs should
further be investigated using the DoE methodology. As a result, a mathematical model is derived
that relates APPs and APAs and is used to compute DS that is considered as a robustness zone in
which no significant changes in APAs occur, regardless of the change in APPs. Such a DS is
achieved by the robust optimization approach in combination with Monte Carlo simulations, which
allow the calculation of the predictive probability for a given APA to be greater th an a desired
threshold. Finally, it is necessary to validate the method and define the system suitability
parameters (SST) to determine the control strategy for the analytical method. The control strategy
should ensure that the analytical method performs as expected when used routinely during its life
cycle.
Conclusions:
When developing the analytical procedure according to the innovative approach:(i) SST parameters
are defined and non-significance intervals for significant factors are estimated, (ii) robustness is
tested - a properly implemented AQbD approach is called robust optimization and (iii) the quality
of the results is guaranteed - DS is the region in which the criteria for APAs are met with a
predefined probability (π). The use of predefined performance characteristics and the associated
acceptance criteria allow the analytical procedure to evolve over the course of its life cycle
Consideration of electrophoretic behavior of some imidazoline and α adrenergic receptors ligands using DFT approach
No full textThe influence of electronic properties of some imidazoline and α-adrenergic receptors
ligands on their electrophoretic behavior, was investigated in DFT study, using B3LYP/6-31G
(d,p) basis set. The values of quantum chemical-based molecular descriptors (chemical potential
(μ), electronegativity (χ), chemical hardness (η), global softness (S), and electrophilicity index (ω))
were considered in terms of relation with the previously determined effective electrophoretic
mobility (µeff) values. Significant relation was observed for descriptors: S, ω, and η, suggesting
on the influence of the ease of polarization and charge redistribution on electrophoretic mobility
of some imidazoline and α-adrenergic receptors ligands
Atomic force microscopy and rheological measurements valuable techniques for describing microstructural organization of ibuprofen nanoemulgels
No full textThis study aimed to investigate the internal organization of ibuprofen nanoemulgels by employing atomic force microscopy and rheological analyses. The objective was to correlate the influence of different gelling agents on the 3D microstructure and viscosity with the resulting drug release kinetics
Identification of Dual-Acting HDAC Inhibitors for Pancreatic Cancer Treatment through Drug Synergy Predictions and Molecular Modeling
No full textBackground: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with chemoresistance playing a significant role in its poor prognosis. This highlights the urgent need for the development of novel therapeutic strategies to overcome resistance and improve treatment outcomes for PDAC [1]. Considering the widespread epigenetic alterations in PDAC, targeting epigenetic regulators such as histone deacetylases (HDACs) with inhibitors is a promising approach, especially in combination therapies [2].
Material and Methods: In this study, we developed a bioinformatic screening protocol to predict potential synergistic combinations of HDAC inhibitors, including sirtuin (SIRT) inhibitors, by utilizing data on drug sensitivity and basal gene expression of pancreatic cancer cell lines.
Results and Conclusions: Experimental validation in two pancreatic cancer cell lines, MIA PaCa-2 and PANC-1, confirmed synergy between HDAC inhibitors and either the sphingosine-1-phosphate (S1P) receptor agonist fingolimod or the Rho-associated protein kinase (ROCK) inhibitor RKI-1447 [3].
The bioinformatic screening also identified several previously unknown interaction partners for HDAC inhibitors, including ROCK, aurora kinase A (AURKA), glutaminase 1(GLS1) and WEE1 kinase inhibitors. These identified interactions were further investigated using structure-based molecular modeling to develop novel dual-acting HDAC inhibitors (HDAC/ROCK, SIRT/AURKA, HDAC/GLS1 and HDAC/WEE1). The molecular docking simulations revealed strong binding affinities of the novel dual-acting HDAC inhibitors to the respective targets. The key structural features responsible for the inhibition of HDAC1/4/6/8, SIRT, ROCK1, ROCK2, AURKA, GLS1 and WEE1 were identified and served as the basis for the development of these dual-acting HDAC inhibitors.
Together with the predictions of drug synergies, these inhibitors prove to be promising candidates for future experimental validation. The most promising dual-acting HDAC inhibitors identified in silico will be synthesized for further in vitro enzyme and cell-based assays.https://www.sdir.ac.rs/abstract-book-sdir-7
Припреме микрокапсула хитосан/натријум-додецил-сулфат: утицај методе припреме
No full textThis study aims to compare and analyse the synthesis of microcapsules stabilized with chitosan/sodium dodecyl sulphate complex according to emulsion preparation methods. For this purpose, 20 % oil-in-water emulsions were obtained in two ways: by emulsifying the oil phase in aqueous solution of chitosan and its mixtures with anionic surfactant (“method I”) and by subsequently dropping chitosan into an already prepared emulsion stabilized by anionic surfactant (“method II”). Good stability, positive zeta potential of the emulsions and uniform droplet size distribution obtained with both methods, enabled the preparation of chitosan-based microcapsules which were separated by spray drying and investigated in terms of yield, moisture content, particle mean diameter and size distribution. The results showed a uniform particle size distribution and approximately equal mean diameters of emulsion droplets (≈ 8 µm), i.e., suspension particles (≈ 5µm), while the microcapsule yields and moisture content for method I were 15 and 1.14 %, and for method II were 1.2 and 2.85 %, respectively. These results indicate that method I may be more suitable for use in the pharmaceutical and food industries for the production of chitosan microcapsules with oil content. The study confirmed that small variations in preparation can lead to large changes in the microencapsulation process and microcapsule structure.Циљ овог рада је упоредна анализа микрокапсула стабилизованих комплексом хито- зан/натријум-додецил-сулфат у зависности од методе припреме емулзијa. У том циљу, 20 % емулзије уље у води добијене су на два начина: емулговањем уљне фазе у воденом раствору хитозана и његових смеша са анјонским сурфактантом („метод I”) и накнадним укапавањем хитозана у већ припремљену емулзију стабилизовану помоћу анјонског сурфактанта („метод II”). Добра стабилност, позитиван зета потенцијал и уједначена расподела величина капи емулзија добијених обема методама, омогућили су припрему хитозанских микрокапсула које су издвојене сушењем распршивањем и којима је одређен принос, садржај влаге, средњи пречник и расподела величине честица. Резултати су пока- зали уједначену распподелу честица по величини и приближно једнаке средње пречнике капи емулзија (≈ 8 μm ), односно суспензија (≈ 5 μm), док су приноси микрокапсула и садржај влаге за метод I били 15 и 1,14 %, а за метод II 1,2 и 2,85 %, редом. Добијени резултати указују да метод I може бити погоднији за производњу хитозанских микро- капсула са уљним језгром у фармацеутској и прехрамбеној индустрији. Студија је пока- зала и да мале варијације у припреми могу довести до великих промена у процесу микрокапсулирања и структури микрокпсула
Endemic Plant Rumex balcanicus: Phenolic Composition, Antioxidant Activity, Enzyme Inhibitory Potential and Molecular Docking Analysis
No full textAlthough the nutritional and health benefits of Rumex species are well known, little is known about the chemical composition and pharmacological activities of Rumex balcanicus Rech. fil. (Polygonaceae), an endemic plant of the Balkan Peninsula. To the best of our knowledge, this paper represents the first attempt to comparatively analyse phenolic composition, as well as in vitro pharmacological activites of dry hydromethanol extracts of R. balcanicus fruit (RBF), leaf (RBL) and root (RBR), collected in Serbia. The maximum total phenolic content was found in RBF (386.6 mg GAE/g). The RBF was characterized by high amounts of miquelianin (28.8 mg/g) and procyanidin B1 (28.1 mg/g). The RBL was the richest in quercitrin (18.4 mg/g) and miquelianin (15.0 mg/g), while nepodin (54.1 mg/g) and procyanidin B2 (40.6 mg/g) were the major compounds in RBR. The RBF exhibited significant antioxidant activity, evaluated by DPPH (IC50=4.9 μg/mL), ABTS (IC50=0.8 μg/mL) and FRAP (5.9 mmol Fe2+/g) assays. Moreover, RBF showed strong α-glucosidase inhibitory activity (IC50=1.8 μg/mL), in addition to notable anti-α-amylase, anti-acetylcholinesterase and anti-tyrosinase activities. Molecular docking analysis predicted miquelianin and procyanidin B2 as the greatest inhibitors of these enzymes. Overall, R. balcanicus fruits stood out as the most promising plant material worth further research