Synthesis, characterization, antitumor potential, and investigation of mechanism of action of copper(ii) complexes with acylpyruvates as ligands: interactions with biomolecules and kinetic study

Considering the urgency of finding a cure for vicious diseases such as tumors, we have synthesized and characterized a small series of new copper(ii) complexes with biologically important ligands such as acylpyruvate. In addition to this, we used another four copper(ii) complexes, with ligands of the same type to examine the antitumor potential. The antitumor potential of the copper(ii) complexes was examined on three tumor cell lines and one normal human cell line using the MTT assay. All seven tested complexes showed very good cytotoxic effects. Two copper complexes that showed the best antitumor potential were selected for further testing that showed the best potential for potential application in the future. The mechanism of activity of these complexes was examined in detail using tests such as cell cycle, ROS level, oxidative DNA damage, and proteins related to hypoxia analysis. In addition, we examined the binding abilities of these complexes with biomolecules (Guo, Ino, 5′-GMP, BSA, and DNA). The results showed that the tested compounds bind strongly to DNA molecules through intercalation. Also, it has been shown that the tested compounds adequately bind to the BSA molecule, which indicates an even greater potential for some future application of these compounds in clinical practice. © 2022 The Royal Society of Chemistry

Primena simulacionih ogledala za procenu kvaliteta budućeg akumulacionog jezera

Većina zemalja u svetu rešava svoje potrebe za kvalitetnom vodom izgradnjom površinskih akumulacija. Zbog grešaka koje su se dešavale usled zanemarivanja svih faktora koji mogu da utiču na kvalitet vode u budućoj akumulacij, dolazilo je do naglog ,,starenja” jezera i na kraju do procesa eutrofikacije. Pogoršavanje kvaliteta jezerske vode može biti takvih razmera da je ekonomski opravdanija izgradnja nove akumulacije, nego eksplatacije stare. Zbog toga se sve više pažnje obraća na uticaj zone potapanja na kvalitet vode u budućoj akumulaciji, a u svetu se čak proizvode i posebne geosintetske podloge koje imaju ulogu smanjenja emisije zagađivača iz zone potapanja u vodu. Od predložene metodologije očekuje se da omogući identifikaciju pojedinačnih uticaja kao i predviđanje uticaja pri sadejstvu u realnom sistemu. Razvojem takve metodologije bilo bi omogućeno da se na hemijskoj osnovi predvide i mere koje treba preduzeti pre izgradnje jezera. Cilj ovog rada je razvijanje analitičke metodologije koja bi predstavljala nov i racionalniji pristup u prognozi rizika od negativnih uticaja sastojaka zemljišta na vodu budućeg akumulacionog jezera

On water synthesis of the novel 2-oxo-1,2,3,4-tetrahydropyrimidines

A simple on water approach for the synthesis of novel tetrahydropyrimidine (THPM) derivatives has been developed under a green and sustainable fashion. For the first time, a deuterated Biginelli's hybrid was synthesized. Novel THPMs are suitable for further derivatization and could be an excellent toolkit for lead-oriented synthesis and/or cross-coupling reactions. (C) 2020 Elsevier Ltd. All rights reserved

Antitumor activity, DNA and BSA interactions of novel copper(II) complexes with 3,4-dihydro-2(1H)-quinoxalinones

In order to discover new therapeutically active agents a series of novel copper(II) complexes with 3,4-dihydro-2(1H)-quinoxalinones were synthesized. All complexes were characterized by IR and EPR spectroscopic techniques and examined for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, three of them were chosen for analysing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that tested complexes lead to time-dependent accumulation of the cells in S and G2/M phases. The strongest accumulation effect showed complex 2d after 48 h of incubation. Competitive experiments with ethidium bromide (EB) indicated that tested compound 2d have affinity to displace EB from the EB-DNA complex through intercalation. Also, the binding parameters values for 2d-BSA complex showed that a reversible 2d-BSA complex is formed and ligand 2d can be stored and carried by BSA

Investigation of the radical scavenging potential of vanillin-based pyrido-dipyrimidines: experimental and in silico approach

Antioxidants have a significant contribution in the cell protection against free radicals which may induce oxidative stress, and permanently damage the cells causing different disorders such as tumors, degenerative diseases, and accelerated aging. Nowadays, a multi-functionalized heterocyclic framework plays an important role in drug development, and it is of great importance in organic synthesis and medicinal chemistry. Encouraged by the bioactivity of the pyrido-dipyrimidine scaffold and vanillin core, herein, we made an effort to thoroughly investigate the antioxidant potential of the vanillin-based pyrido-dipyrimidines A–E to reveal novel promising free radical inhibitors. The structural analysis and the antioxidant action of the investigated molecules were performed in silico by DFT calculations. Studied compounds were screened for their antioxidant capacity using in vitro ABTS and DPPH assays. All the investigated compounds showed remarkable antioxidant activity, especially derivative A exhibiting inhibition of free radicals at the IC50 value (ABTS and DPPH assay 0.1 mg ml−1 and 0.081 mg ml−1, respectively). Compound A has higher TEAC values implying its stronger antioxidant activity compared to a trolox standard. The applied calculation method and in vitro tests confirmed that compound A has a strong potential against free radicals and may be a novel candidate for application in antioxidant therapy

Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions

Selected tetrahydropyrimidines (THPMs) were investigated by means of cytotoxic activities on selected cancer (HeLa, A549, and LS174) and non-cancerous cell lines (MRC-5). Among evaluated compounds, two of them ( B7 and B8 ) showed good cytotoxic activity on the tested cell lines and were selected for fur- ther evaluation that included mechanism of action, DNA and BSA interactions and molecular docking study. Calculated parameters from fluorescence quenching studies indicated that B7 and B8 bind on mi- nor groove of DNA and have great ability to bind on carrier protein. Three-dimensional quantitative struc- ture anti-HeLa activity study was performed with data set of THPMs. Molecular Interaction Fields were used to derive Grid independent descriptors (GRIND), as independent variables in Pentacle software. The quality and predictive capacity of the model was proved by internal statistical parameters: R 2 = 0.992, Q 2 = 0.51, as well as external parameters such as R 2 pred = 0.804 and r m 2 , r / 2 m and r 2 m , that were higher than 0.5. The structural determinants significant for anti-HeLa activity of compounds were identified by using developed 3D-QSAR model. Interpretation of the most impactful GRIND variables on the anti-HeLa activity generated several hypotheses for design of novel and more potent anti-HeLa tetrahydropyrim- idines. Additional molecular targets for the most active synthesized derivatives ( B7 and B8 ) are predicted by use of online web-based tool-SwissTargetPrediction

Anticancer potential of some <i>β</i>-diketonates: DNA interactions, protein binding properties, and molecular docking study

With the goal to discover a new antitumor drug with the better or similar effects to existing, a small series of β-diketonate was tested on a cisplatin-resistant MDA-MB-231 and HeLa tumor cell lines, and nontumor MRC-5 cell line. All compounds showed notable cytotoxicity against both tumor cell lines and good selectivity. Importantly, β-diketonates displayed greater selectivity than cisplatin, which is the crucial factor for a new antitumor drug candidate. Further, investigations with biomacromolecules such as DNA and serum albumin were performed. Investigations showed that tested compounds bind to DNA through intercalation and have appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of tested β-diketonate to DNA or bovine serum albumin. In conclusion, all results indicated the big potential of these compounds for application in clinical practice in future.</p