Synthesis, characterisation, teoretical and biological examinations of palladium(II) ion complexes with ethylenediamine derivatives of tryptophan and substituted 2-aminothiazoles

[S. S. Jovičić Milić]

97, [19] listova

U okviru ove doktorske disertacije opisana je sinteza, karakterizacija i biološka aktivnost O,O′-dialkil estara (S,S)-etilendiamin-N,N′-di-(3,3′-1H-indol-3- -il) propionske kiseline dihlorhidrata (L1-L4) kao liganada i njihovih paladijum(II) kompleksa (C1-C4), kao i kompleksa paladijum(II) jona sa 2-amino-6- -metilbenzotiazolom (C5) i 2-amino-6-hlorobenzotiazolom (C6). Karakterizacija novosintetisanih jedinjenja vršena je na osnovu rezultata elementalne mikroanalize i spektroskopskih metoda (IR, 1H i 13C NMR) i metodom rendgenske strukturne analize (C6). In vitro antimikrobna aktivnost svih liganada i njihovih paladijum(II) kompleksa određena je testiranjem na 19 mikroorganizama. In vitro antitumorska aktivnost liganada L1-L4 i kompleksa C1-C4 je određena testiranjem na ćelijama humanog i mišijeg karcinoma debelog creva (HCT116 i CT26), dok je za liganade L5-L6 i komplekse C5-C6 određena na mišijim ćelijama karcinoma dojke 4T1, ćelijama mišijeg kolorektalnog karcinoma CT26, normalne linije mezenhimalnih matičnih ćelija miša mMSC i humanim ćelijama karcinoma dojke MDA-MB-468, kao i humanog kolorektalnog karcinoma HCT116. Za proučavanje reakcija supstitucije paladijum(II) kompleksa sa derivatima 2-aminotiazola korišćeni su konstituent DNA (5’GMP), tripeptid glutation (GSH) i aminokiselina (L-Met), a reakcije su izučavane pomoću stopped-flow metode. U cilju potvrđivanja načina vezivanja između svih ispitivanih kompleksa paladijuma(II) i CT-DNA, vršena su merenja viskoznosti rastvora u prisustvu i u odsustvu svakog kompleksa, a na osnovu rezultata može se zaključiti da dolazi do interakcije putem interkalacije. Za bolje razumevanje inhibitorne aktivnosti paladijum(II) kompleksa C1-C4 primenjene su molekulske doking simulacije i to korišćenjem programskog paketa AutoDock 4.2

The synthesis, characterization and biological activity of O,O′-dialkyl esters of (S,S)-ethylenediamine-N,N′-di-(3,3′-1H-indol-3-yl) propionate acid dihydrochloride (L1-L4) as ligands and their palladium(II) complexes (C1-C4), as well as complexes of palladium(II) ions with 2-amino-6-methylbenzothiazole (C5) and 2-amino-6-chlorobenzothiazole (C6) are described in this doctoral dissertation. The characterization of newly synthesized compounds was performed based on the results of elemental microanalysis and spectroscopic methods (IR, 1H and 13C NMR) and using the X-ray structural analysis (C6). In vitro antimicrobial activity of all ligands and their palladium(II) complexes was determined being tested on 19 microorganisms. In vitro antitumor activity of ligands L1-L4 and complexes C1-C4 was determined being tested on human and murine colon cancer cells (HCT116 and CT26, while the antitumor activity of ligands L5-L6 and complexes C5-C6 was determined on mouse breast cancer cells 4T1, mouse colorectal cancer cells CT26, normal mouse mesenchymal stem cell line mMSC and human breast cancer cells MDA-MB-468 as well as human colorectal cancer HCT116. In order to study substitution reactions of palladium(II) complexes with 2-aminothiazole derivatives (C5 and C6) DNA constituent (5'GMP), tripeptide glutathione (GSH) and amino acid (L-Met) were used and the reactions were studied using the stoppedflow method In order to confirm the method of binding between all examined palladium(II) complexes and CT-DNA, the viscosity of the solution was measured in the presence and in the absence of each complex; based on the results the interaction was concluded to occur through intercalation. For a better understanding of the inhibitory activity of the palladium(II) complex (C1-C4), molecular docking simulations were applied using the AutoDock 4.2 software package.

Kompleksi paladijum(II) jona, ligandi edda tipa, derivati 2-aminotiazola, DFT, antimikrobna aktivnost, citotoksička aktivnost, kinetika, interakcije, metoda molekulskog dokinga

Palladium(II) complexes, edda-type ligands, derivatives of 2-aminothiazole, DFT, antimicrobial activity, cytotoxic activity, kinetics, interactions, molecular docking method

546.98:547.582(043.3)

Tekst