New ruthenium complexes containing salicylic acid and derivatives induce triple-negative tumor cell death via the intrinsic apoptotic pathway

• Published in: European journal of medicinal chemistry Vol. 243; p. 114772
• Main Authors: Graminha, Angelica E., Popolin, Cecília, Honorato de Araujo-Neto, João, Correa, Rodrigo S., de Oliveira, Kátia M., Godoy, Luani R., Vegas, Legna Colina, Ellena, Javier, Batista, Alzir A., Cominetti, Marcia R.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05-12-2022
• Subjects: Cell death; Cytotoxicity; Ruthenium complexes; Salicylic acids; Salicylic acids; Cytotoxicity; Ruthenium complexes; Cell death
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114772

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF6 and [Ru(L)(dppe)2]PF6 where L = salicylic acid (Sal), 4-aminosalicylic acid (AmSal) or 2,4-dihydroxybenzoic acid (DiSal), dppb = 1,4-bis(diphenylphosphino)butane, dppe = 1,2-bis(diphenylphosphino)ethane and bipy = 2,2′-bipyridine. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR, UV–vis and IR spectroscopies, and two by X-ray crystallography. The 31P{1H} NMR spectra of the complexes with the general formula [Ru(L)(dppe)2]PF6 showed that the phosphorus signals are solvent-dependent. Aprotic solvents, which form strong hydrogen bonds with the complexes, inhibit the free rotation of the salicylic acid-based, modifying the diphosphine cone angles, leading to distortion of the phosphorus signals in the NMR spectra. The cytotoxicity of the complexes was evaluated in MCF-7, MDA-MB-231, SKBR3 human breast tumor cells, and MCF-10 non-tumor cell lines. The complexes with the structural formula [Ru(L)(dppe)2]PF6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe)2]PF6 with L = 4-aminosalicylic acid ligand was the most selective for the MDA-MB-231 cell line. This complex interacts with the transferrin and induces apoptosis through the intrinsic pathway, as demonstrated by increased levels of proteins involved in apoptotic cell death.
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•Six Ru(II) complexes of salicylic acid and derivatives were synthesized.•Complex [Ru(AmSal)(dppe)2]PF6 – Ru(5) was the most selective against TNBC.•Ru(5) inhibited colony formation by acting as a cytotoxic and cytostatic agent.•Ru(5) induced tumor cells apoptosis, altering the mitochondrial membrane potential.•Ru (5) induced cell death through intrinsic apoptotic pathway signaling.