Sinteza, karakterizacija i ispitivanje biološke aktivnosti kompleksa bakra(II) sa S,O-tetradentatnim ligandima, derivatima tiosalicilne kiseline

Abstract

Uvod: Terapijska primena kompleksa bakra(II) privlači pažnju istraživača zbog mogućnosti koordinovanja sa različitim donorskim atomima. Među liganadima koji u strukturi sadrže sumpor i kiseonik izdvaja se tiosalicilna kiselina, čiji derivati pokazuju citotoksičnost u terapiji tumora. Materijal i metode: U ovoj Doktorskoj disertaciji opisani su sinteza S,O tetradentatnih liganada, derivata tiosalicilne kiseline i kompleksa bakra(II) sa navedenim ligandima. Radi potvrde njihove strukture, sprovedena su različita merenja: mikroanaliza, infracrvena spektroskopija, nuklearno-magnetno-rezonanciona spektroskopija, elektronska paramagnetna rezonancija i molarna provodljivost. U cilju procene biološke aktivnosti sprovedene su nukleofilne supstitucione reakcije kompleksa sa endogenim ligandima (L-metioninom, L-cisteinom i 5’-GMP), in vitro interakcije sa ST-DNK (eng. calf thymus, DNK timusa govečeta) i humanim serumskim albuminom (HSA) pomoću apsorpcione spektroskopske analize i emisione fluorescencije, in silico interakcije sa DNK i HSA. Takođe, primenom MTT kolorimetrijskog testa analizirana je citotoksičnost sintetisanih liganada i kompleksa na tri ćelijske linije. Rezultati: Analizom sprovedenih merenja pretpostavljena je oktaedarska geometrija kompleksa. Svi kompleksi podležu reakcijama nukleofilne supstitucije. Visoke vrednosti konstante vezivanja pokazuju da kompleksi interaguju sa molekulom DNK i HSA. Interakcija sa DNK molekulom dešava se interkalacijom ili interakcijom sa malim žlebom. Kompleksi imaju citotoksični potencijal, dok je prema svim ćelijskim linijama najbolju citotoksičnost na osnovu IC50 vrednosti pokazao kompleks [Cu(S,O-pentilen-tiosalicilna kiselina)].

Introduction: The therapeutic application of copper(II)-complexes attracts the attention of researchers due to the possibility of coordination with different donor atoms. Among the ligands that contain sulfur and oxygen in the structure, thiosalicylic acid stands out, whose derivatives show cytotoxicity in tumor therapy. Material and methods: In this Doctoral dissertation, the synthesis of S,O-tetradentate ligands, derivatives of thiosalicylic acid and copper(II)-complexes with the mentioned ligands is described. In order to confirm their structure, various measurements were performed: microanalysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, electronic paramagnetic resonance and molar conductivity. In order to assess biological activity, nucleophilic substitution reactions of complexes with endogenous ligands (L-methionine, Lcysteine and 5'-GMP), in vitro interactions with ct-DNA (calf thymus DNA) and human serum albumin (HSA) were performed by absorption spectroscopic analysis and emission fluorescence, in silico interactions with DNA and HSA. Also, the cytotoxicity of synthesized ligands and complexes on three cell lines was analyzed using MTT colorimetric test. Results: The octahedral geometry of the complex was assumed by the analysis of the performed measurements. All complexes react to nucleophiles. High values of the binding constant indicate that the complexes interact with the DNA molecule and HSA. Interaction with a DNA molecule occurs by intercalation or interaction with a small groove. The complexes have cytotoxic potential, while the [Cu (S,O-pentylene-thiosalicylic acid)] complex showed the best cytotoxicity based on IC50 values according to all cell lines. Keywords: S,O-tetradentate ligands, copper(II) complexes, interactions, molecular docking, antitumor activity