Sinteza, karakterizacija i ispitivanje biološke aktivnosti kompleksa bakra(II) sa ß-aminokiselinama
Synthesis, characterization and biological activity examination of copper(II) complexes with β-amino acid
Author
Bukonjić, Andriana M.
Mentor
Bogojeski, Jovana
Committee members
Arsenijević, Nebojša
Sabo, Tibor

Radić, Gordana
Jevtić, Verica
Metadata
Show full item recordAbstract
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 coppe...r(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.
Faculty:
Универзитет у Крагујевцу, Факултет медицинских наукаDate:
31-01-2019Projects:
- Preclinical investigation of bioactive substances (RS-41010)
- Synthesis, modeling, physicochemical and biological properties of organic compounds and related metal complexes (RS-172016)