In vitro antitumor activity, metal uptake and reactivity with ascorbic acid and BSA of some gold(III) complexes with N,N′-ethylenediamine bidentate ester ligands

Abstract

Four novel gold(III) complexes of general formulae [AuCl{(S,S)-Reddl}]PF (Reddl=O,O'-dialkyl-(S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoate, R=n-Pr, n-Bu, n-Pe, i-Bu; 1-4, respectively), were synthesized and characterized by elemental analysis, UV/Vis, IR, and NMR spectroscopy, as well as high resolution mass spectrometry. Density functional theory calculations pointed out that (R,R)-N,N'-configuration diastereoisomers were energetically the most favorable. Duo to high cytotoxic activity complex 3 was chosen for stability study in DMSO, no decomposition occurs within 24h, and for the reaction with ascorbic acid in which was reduced immediately. Additionally, 3 interacts with bovine serum albumin (BSA) as proven by UV/Vis spectroscopy. In vitro antitumor activity was determined against human cervix adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human melanoma (Fem-x) cancer cell lines, as well as against non-cancerous human embryonic lung fibroblast cells MRC-5. The highest activity was observed against K562 cells (IC: 5.04-6.51μM). Selectivity indices showed that these complexes are less toxic than cisplatin. 3 had a similar viability kinetics on HeLa cells as cisplatin. Drug accumulation studies in HeLa cells showed that the total gold uptake increased much faster than that of cisplatin pointing out that 3 more efficiently enters the cells than cisplatin. Furthermore, morphological and cell cycle analysis reveal that gold(III) complexes induced apoptosis in time- and dose-dependent manner.

Design and In Vitro Biological Evaluation of a Novel Organotin(IV) Complex with 1-(4-Carboxyphenyl)-3-ethyl-3-methylpyrrolidine-2,5-dione

“…Chemical shifts for 1 H, 13 C, and spectra were referenced to internal standard TMS. Mass spectra of the compound were recorded with an Orbitrap LTQ XL instrument ( ermo Scientific, Bremen, Germany) in CH 3 CN [57]. Reagents and solvents were of commercial reagent grade quality and used without further purification.…”

“…Survival. Similarly to methods described in [57], HeLa (2500 cells/well) and MDA-MB-453 cells (3000 cells/well) were seeded into the wells of a 96well flat-bottomed microtiter plate. Twenty-four hours later, after the cell adherence, different concentrations of investigated compounds were added to the wells, except for the controls, where only the complete medium was added.…”

“…e ligand concentration range used was 12.5-200 µM. e final concentration of DMSO was negligible for complex and never exceeded 1% for ligand, which is a nontoxic concentration for the cells [57]. For nonadherent K562 cells (5000 cells/well), the compounds were applied 2 h after cell seeding.…”

“…Afterward, 100 mL of 10 sodium dodecyl sulfate (SDS) was added in order to extract the insoluble formazan, which represents the product of the conversion of the MTT dye by viable cells. e number of viable cells in each well is proportional to the intensity of the absorbance (A) of light, which was measured in a microtiter plate reader at 570 nm, 24 h later [57]. To determine cell survival (%), the A of a sample with cells grown in the presence of various concentrations of the investigated compounds was divided by the control optical density (the A of control cells grown only in the nutrient medium) and multiplied by 100. e A of the blank was always subtracted from the A of the corresponding sample incubated with the target cells.…”

“…To determine cell survival (%), the A of a sample with cells grown in the presence of various concentrations of the investigated compounds was divided by the control optical density (the A of control cells grown only in the nutrient medium) and multiplied by 100. e A of the blank was always subtracted from the A of the corresponding sample incubated with the target cells. IC 50 is defined as the concentration of an agent inhibiting cell survival by 50% compared with the vehicle-treated control [57]. All experiments were performed in technical and biological triplicates.…”