Studies on the mechanism of action of anti-tumor bis(aminophenolate) ruthenium(III) complexes

Dömötör, Orsolya and de Almeida, Rodrigo F M and Côrte-Rea, Leonor and Matos, Cristina P. and Marques, Fernanda and Enyedy, Éva Anna and Matos, António and Kiss, Tamás and Real, Carla and Garcia, Helena and Tomaz, Ana Isabel (2017) Studies on the mechanism of action of anti-tumor bis(aminophenolate) ruthenium(III) complexes. JOURNAL OF INORGANIC BIOCHEMISTRY, 168. pp. 27-37. ISSN 0162-0134

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Abstract

Two recently published Ru(III) comp lexes bearing ( N 2 O 2 ) tetradentate bis(aminophenolate) ligands, 20 formulated as [Ru(III)( s alan )(PPh 3 )Cl] ( where s alan is the tetradentate ligand 6,6' - (1S,2S) - 21 cyclohexane - 1,2 - diylbis(azanediyl)bis(met hylene)bis(3 - methoxyphenol) in c omplex 1 , or 2,2' - (1S,2S) - 22 cyclohexane - 1,2 - diylbis(azanediyl)bis(meth ylene)bis(4 - methoxyphenol) in c omplex 2 , and PPh 3 is 23 triphenylphosphane ) were studied herein to outline their antitumor mode of action. Previously, it was 24 found that they were very active against human ovar ian and bre a st adenocarcinoma cells (on a 72 h 25 challenge ) . In this work, the human cisplatin - sensitive o varian adeno carcinoma line A2780 was used 26 as the cell model for further studies a t a 24 h challenge . B oth complexes are active , their cytotoxicity 27 being c omparable to that of c isplatin in the same conditions. 28 A s a possible target in the cell for their action, the int eraction of 1 and 2 with DNA was assessed 29 through displacement of well - established DNA fluorescent probes ( ethidium bromide , EB, and 4',6 - 30 d iamidino - 2 - p henylindole, DAPI ) through s teady - state and time - resolved fluorescence spectroscopy . 31 The complete emission spectra were analysed globally for the binary DNA ‒ p robe and ternary DNA ‒ 32 p robe ‒ Ru(III) complex systems . B oth Ru(III) complexes can displace EB and bind to DNA with 33 similar and moderate strong affinity with conditional stability constants of log K’ = ( 5.05 ± 0.01 ) for 1 34 and log K’= ( 4.79 ± 0.01 ) for 2 . The analysis of time - domain fluorescence intensity decays confirmed 35 both qualitatively and quantitatively the model used to describe the binding and competition processes. 36 Cell studies indicated that apoptosis is t he major mechanism of cell death for both complexes , with 2 37 (the mo re active complex ) promoting that process more efficiently than 1 . Transmission electron 38 micro graphs revealed clear a lteration s on intracellular organization consistent with the induction of 39 programmed cell death processes.

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