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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.

In order to discover new dual-active agents, a series of novel Biginelli hybrids (tetrahydropyrimidines) and their ruthenium(II) complexes were synthesized. Newly synthesized compounds were characterized by IR, NMR, and X-ray techniques and investigated for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549, A375, K562 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, two of them were chosen for analyzing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that the proportion of cells in G2/M phase was decreased following the increase of subG1 phase in all treatments. These results confirmed that cells treated with 5b and 5c were induced to undergo apoptotic death. The ruthenium complexes 5a-5d show significant inhibitory potency against SARS-CoV-2 Mpro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔGbind and Ki, which are comparable to cinanserin, and hydroxychloroquine. In addition, achieved results will open a new avenue in drug design for more research on the possible therapeutic applications of dual-active Biginelli-based drugs (anticancer-antiviral). Dual-active drugs based on the hybridization concept “one drug curing two diseases” could be a successful tactic in healing patients who have cancer and the virus SARS-CoV-2 at the same time.

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 further 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 minor groove of DNA and have great ability to bind on carrier protein. Three-dimensional quantitative structure 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: R2 = 0.992, Q2= 0.51, as well as external parameters such as R2 pred = 0.804 and rm2, r/ 2 m and r2 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 tetrahydropyrimidines. Additional molecular targets for the most active synthesized derivatives (B7 and B8) are predicted by use of online web-based tool-SwissTargetPrediction.

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 complex2dafter 48h of incubation. Competitive experiments withethidium bromide(EB) indicated that tested compound2dhave affinity to displace EB from the EB-DNA complex throughintercalation. Also, the binding parameters values for2d-BSA complex showed that a reversible2d-BSA complex is formed and ligand2dcan be stored and carried byBSA.

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.