Docking studies, cytotoxicity evaluation and interactions of binuclear copper(ii) complexes with s-isoalkyl derivatives of thiosalicylic acid with some relevant biomolecules

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5′-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver

Synthesis, characterization and biological activity examination of copper(II) complexes with β-amino acid

Uvod: Bakar(II)-jon je zbog prelazno tvrdo-mekih karakteristika idealan za koordinovanje sa različitim donorskim atomima, a zbog esencijalne uloge koju ima u organizmu njegovi kompleksi su potencijalno manje toksični. Aminokiseline preko atoma azota i kiseonika lako formiraju koordinativno-kovalentne veze sa prelaznim metalima. Zbog biološke aktivnosti i farmakološkog značaja, β-aminokiseline su pogodni ligandi u sintezi potencijalnog leka. Materijal i metode: U okviru ove doktorske disertacije opisani su postupci sinteza β-aminokiselina i odgovarajućih kompleksa bakra(II) sa β-aminokiselinama. Strukture sintetisanih liganada potvrđene su na osnovu infracrvene (IR) i nuklearno- -magnetno-rezonancione spektroskopije (1N i 13S NMR), dok su sastav i strukture sintetisanih kompleksnih jedinjenja pretpostavljene na osnovu rezultata elementalne mikroanalize, infracrvene i elektronsko-paramagnetno-rezonancione spektroskopije (EPR). Stvarna struktura kompleksa bakar(II)-jona i 2-(1-aminocikloheksil)sirćetne kiseline potvrđena je i na osnovu rezultata rendgenske strukturne analize. Interakcije sintetisanih kompleksa sa molekulom DNK utvrđene su na osnovu kinetičkih merenja, apsorpciono spektroskopskih merenja, fluorescentnih merenja i merenja viskoziteta DNK rastvora. Broj i vijabilnost tumorskih ćelija (4T1, CT26, LLC1) nakon primene rastvora kompleksnih jedinjenja određena je kolorimetrijskim MTT testom. Antimikrobna aktivnost sintetisanih jedinjenja ispitana je mikrodilucionom metodom. Rezultati: Potvrđena je kvadratno-planarna struktura sinetisanih kompleksa. Vrednosti konstanti vezivanja, smanjenja intenziteta fluorescencije i povećanje relativnog viskoziteta rastvora DNK ukazuju na interakciju kompleksa i molekula DNK. Od ispitivanih ćelijskih linija najveću osetljivost prema sintetisanim kompleksima pokazale su ćelije karcinoma pluća, LLC1. Oba kompleksa indukuju apoptozu ćelija karcinoma kolona (ST26) i pri nižim koncentracijama imaju bolju aktivnost od cisplatine. Ispitivane supstance ispoljavaju nisku i selektivnu antimikrobnu aktivnost koja je verovatno posledica njihovih slabih lipofilnih karakteristika. Zaključak: Sinteza kompleksa bakra(II) sa različitim ligandima daje mogućnost razvoja potencijalnih lekova. Ispitivanje biološke aktivnosti svakog potencijalnog farmakoterapeutika omogućava da se približnije poveže struktura kompleksa sa mehanizmom dejstva i antitumorskim i antimikrobnim potencijalom.Introduction: Copper(II)-ion is ideal for coordinating with different donor atoms due to its soft-hard characteristics while transferring, and because of its essential role in organism, its complexes are potentially less toxic. Amino acids, through the atoms of nitrogen and oxygen, easily form coordinate-covalent bonds with transition metals. β-amino acids are suitable ligands in the synthesis of a potential medicine because of their biological activity and pharmacological significance. Materials and methods: This PhD thesis describes the syntheses procedures of β-amino acids and corresponding copper(II)-complexes with β-amino acids. The structures of synthesized ligands were confirmed based on infrared (IR) and nuclear-magnetic-resonance spectroscopy (1Н and 13С NMR), while the composition and the structures of synthesized complex compounds were assumed by the results of elemental microanalysis, infrared and electron paramagnetic resonance (EPR). The real structure of copper(II)-ion complex and 2-(1-aminocyclohexyl) acetic acid was confirmed from the results of Roentgen structural analysis. The interactions of synthesized complexes with the DNA molecule were determined by kinetic measurements, absorption spectroscopic measurements, fluorescent measurements and the measurements of the DNA solution viscosity. The number and the viability of tumor cells (4T1, CT26, LLC1), after applying complex compounds solutions, was determined by МТТ colorimetric technique. Antimicrobial activity of synthesized compounds was examined using microdilution method. Results: Square planar structure of synthesized compounds was confirmed. The values of binding constants, fluorescence intensity reduction and the increase of relative DNA solution viscosity indicated the interaction between complexes and the DNA molecule. From the tested cell lines, lung cancer cells (LLC1) showed the largest sensitivity towards synthesized complexes. Both complexes induced cell apoptosis of colon cancer (СТ26) and had higher activity in lower concentrations than cisplatin. The tested substances expressed low and selective antimicrobial activity which was probably the result of their weak lipophilic characteristics. Conclusion: The synthesis of copper(II)-complexes with different ligands offers the possibility for the development of potential medicines. Biological activity examination of each potential drug enables more approximate connection of the structure of complexes with the mechanism of action and anticancer and antimicrobial potentials

Synthesis, characterization and biological activity examination of copper(II) complexes with β-amino acid

Uvod: Bakar(II)-jon je zbog prelazno tvrdo-mekih karakteristika idealan za koordinovanje sa različitim donorskim atomima, a zbog esencijalne uloge koju ima u organizmu njegovi kompleksi su potencijalno manje toksični. Aminokiseline preko atoma azota i kiseonika lako formiraju koordinativno-kovalentne veze sa prelaznim metalima. Zbog biološke aktivnosti i farmakološkog značaja, β-aminokiseline su pogodni ligandi u sintezi potencijalnog leka. Materijal i metode: U okviru ove doktorske disertacije opisani su postupci sinteza β-aminokiselina i odgovarajućih kompleksa bakra(II) sa β-aminokiselinama. Strukture sintetisanih liganada potvrđene su na osnovu infracrvene (IR) i nuklearno- -magnetno-rezonancione spektroskopije (1N i 13S NMR), dok su sastav i strukture sintetisanih kompleksnih jedinjenja pretpostavljene na osnovu rezultata elementalne mikroanalize, infracrvene i elektronsko-paramagnetno-rezonancione spektroskopije (EPR). Stvarna struktura kompleksa bakar(II)-jona i 2-(1-aminocikloheksil)sirćetne kiseline potvrđena je i na osnovu rezultata rendgenske strukturne analize. Interakcije sintetisanih kompleksa sa molekulom DNK utvrđene su na osnovu kinetičkih merenja, apsorpciono spektroskopskih merenja, fluorescentnih merenja i merenja viskoziteta DNK rastvora. Broj i vijabilnost tumorskih ćelija (4T1, CT26, LLC1) nakon primene rastvora kompleksnih jedinjenja određena je kolorimetrijskim MTT testom. Antimikrobna aktivnost sintetisanih jedinjenja ispitana je mikrodilucionom metodom. Rezultati: Potvrđena je kvadratno-planarna struktura sinetisanih kompleksa. Vrednosti konstanti vezivanja, smanjenja intenziteta fluorescencije i povećanje relativnog viskoziteta rastvora DNK ukazuju na interakciju kompleksa i molekula DNK. Od ispitivanih ćelijskih linija najveću osetljivost prema sintetisanim kompleksima pokazale su ćelije karcinoma pluća, LLC1. Oba kompleksa indukuju apoptozu ćelija karcinoma kolona (ST26) i pri nižim koncentracijama imaju bolju aktivnost od cisplatine. Ispitivane supstance ispoljavaju nisku i selektivnu antimikrobnu aktivnost koja je verovatno posledica njihovih slabih lipofilnih karakteristika. Zaključak: Sinteza kompleksa bakra(II) sa različitim ligandima daje mogućnost razvoja potencijalnih lekova. Ispitivanje biološke aktivnosti svakog potencijalnog farmakoterapeutika omogućava da se približnije poveže struktura kompleksa sa mehanizmom dejstva i antitumorskim i antimikrobnim potencijalom.Introduction: Copper(II)-ion is ideal for coordinating with different donor atoms due to its soft-hard characteristics while transferring, and because of its essential role in organism, its complexes are potentially less toxic. Amino acids, through the atoms of nitrogen and oxygen, easily form coordinate-covalent bonds with transition metals. β-amino acids are suitable ligands in the synthesis of a potential medicine because of their biological activity and pharmacological significance. Materials and methods: This PhD thesis describes the syntheses procedures of β-amino acids and corresponding copper(II)-complexes with β-amino acids. The structures of synthesized ligands were confirmed based on infrared (IR) and nuclear-magnetic-resonance spectroscopy (1Н and 13С NMR), while the composition and the structures of synthesized complex compounds were assumed by the results of elemental microanalysis, infrared and electron paramagnetic resonance (EPR). The real structure of copper(II)-ion complex and 2-(1-aminocyclohexyl) acetic acid was confirmed from the results of Roentgen structural analysis. The interactions of synthesized complexes with the DNA molecule were determined by kinetic measurements, absorption spectroscopic measurements, fluorescent measurements and the measurements of the DNA solution viscosity. The number and the viability of tumor cells (4T1, CT26, LLC1), after applying complex compounds solutions, was determined by МТТ colorimetric technique. Antimicrobial activity of synthesized compounds was examined using microdilution method. Results: Square planar structure of synthesized compounds was confirmed. The values of binding constants, fluorescence intensity reduction and the increase of relative DNA solution viscosity indicated the interaction between complexes and the DNA molecule. From the tested cell lines, lung cancer cells (LLC1) showed the largest sensitivity towards synthesized complexes. Both complexes induced cell apoptosis of colon cancer (СТ26) and had higher activity in lower concentrations than cisplatin. The tested substances expressed low and selective antimicrobial activity which was probably the result of their weak lipophilic characteristics. Conclusion: The synthesis of copper(II)-complexes with different ligands offers the possibility for the development of potential medicines. Biological activity examination of each potential drug enables more approximate connection of the structure of complexes with the mechanism of action and anticancer and antimicrobial potentials

Factors influencing knowledge transfer from faculty to PhD students

A phenomenon that does not quite rise to the level of research misconduct occurs when faculty responsible for assisting PhD students fail to fulfill that role. The factors that may affect readiness of faculty to help PhD students with a methodological issue concerning sampling that was essential for designing a dissertation were revealed in this study - a simulated student-professor interaction study. Of 153 faculty asked to assist, 47% failed to respond and of those who responded, only 21% made an appointment to help the student. Results of our study showed that responsible behavior of university professors in regard to helping PhD students was more likely if the faculty member was younger, had more recently been employed and had higher publication and citation scores

Translation to Serbian, cultural adaptation, reliability testing and validation of the questionnaire estimating the fear of injections

Background/Aim. The two-part questionnaire called Injection Phobia Scale (IPS)-Anxiety and IPS-Avoidance represents one of the most commonly used questionnaires for assessing the fear of injections. The aim of the present study was to translate and culturally adapt this questionnaire from English into Serbian as well as to assess reliability and validity of the translation. Methods. The translation and cultural adaptation of the IPS–Anxiety and IPS–Avoidance was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Reliability testing, factor analysis and validation of Serbian translation of IPS-Anxiety and IPS-Avoidance were carried out on a sample of 485 students of pharmacy, or medicine at the University of Kragujevac, Serbia. Results. Serbian translation of IPS-Anxiety and IPSAvoidance demonstrated high internal consistency with Cronbach’s alpha of 0.934 for IPS-Anxiety and 0.911 for IPS-Avoidance. Factor analysis of IPS-Anxiety showed that there are two domains, which we have called as Direct Experience (9 items) and Indirect Experience (9 items); factor analysis of IPS-Avoidance also pointed out on two domains referring to direct and indirect fear of injections. Female students scored higher on the scale showing more extensive injection phobia than male students. It is also interesting that students of pharmacy have higher level of injection phobia than students of medicine, and those students of the fifth year of study feel more fear of injections than students from the first four years. Conclusion. Serbian translation of IPS-Anxiety and IPS-Avoidance showed good psychometric properties on population consisted of students medicine and pharmacy. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175007

Interactions of binuclear copper(II) complexes with S-substituted thiosalicylate derivatives with some relevant biomolecules

Interactions of copper(II) complexes which contain S-alkyl derivatives of thiosalicylic acid (alkyl = methyl, ethyl, propyl and butyl; aryl = benzyl), marked as 1–5, with guanosine-5′-monophosphate (5′-GMP) and calf thymus DNA (CT-DNA) were studied. Kinetics of substitution reactions of 1–5 with 5′-GMP and CT-DNA were investigated under pseudo-first-order conditions at 310 K and pH = 7.2 in 25 mM Hepes buffer using stopped-flow method. All complexes have high affinity toward studied bio-molecules. Additionally, interactions with CT-DNA were followed by absorption spectroscopy and fluorescence quenching measurements. The results indicate that complexes bind to DNA exhibiting high binding constants (Kb = 104 M−1). During the examination of competitive reactions with ethidium bromide (EB), results showed that complexes can replace EB-bound DNA. In addition, a new crystal structure of the binuclear Cu(II) complex with S-substituted thiosalicylate derivative has been reported. In the present series of Cu(II) complexes the crystal structure is the first example of a complex comprising an S-aryl derivative of thiosalicylate ligand. Through comparative study of structural properties of six molecules from four crystal structures we examined the structural variations, potentially important for biological activity of these complexes. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group