Synthesis, chemical characterization, PARP inhibition, DNA binding and cellular uptake of novel ruthenium(II)-arene complexes bearing benzamide derivatives in human breast cancer cells

• Published in: Journal of inorganic biochemistry 2020-09, Vol.210, p.111155-111155, Article 111155
• Main Authors: Pavlović, Marijana, Tadić, Ana, Gligorijević, Nevenka, Poljarević, Jelena, Petrović, Tamara, Dojčinović, Biljana, Savić, Aleksandar, Radulović, Siniša, Grgurić-Šipka, Sanja, Aranđelović, Sandra
• Format: Article
• Language: English
• Subjects: Antitumor agents; Breast cancer; PARP inhibitor; Ruthenium(II)
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2020.111155

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) showed remarkable clinical efficacy in BRCA-mutated tumors. Based on the rational drug design, derivatives of PARP inhibitor 3-aminobenzamide (3-AB), 2-amino-4-methylbenzamide (L1) and 3-amino-N-methylbenzamide (L2), were coordinated to the ruthenium(II) ion, to form potential drugs affecting DNA and inhibiting PARP enzyme. The four conjugated complexes of formula: C1 [(ƞ6-toluene)Ru(L1)Cl]PF6, C2 [(ƞ6-p-cymene)Ru(L1)Cl]PF6, C3 [(ƞ6-toluene)Ru(L2)Cl2] and C4 [(ƞ6-p-cymene)Ru(L2)Cl2], have been synthesized and characterized. Colorimetric 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) assay showed the highest antiproliferative activity of C1 in HCC1937, MDA-MB-231, and MCF-7 breast cancer cells. Efficiency of inhibition of PARP-1 enzymatic activity in vitro decreased in order: C2 > C4 > 3-AB>C1 > C3. ICP-MS study of intracellular accumulation and distribution in BRCA1-mutated HCC1937 revealed that C1-C4 entered cells within 24 h. The complex C1 showed the highest intracellular accumulation, nuclear-targeting properties, and exhibited the highest DNA binding (39.2 ± 0.6 pg of Ru per μg of DNA) that resulted in the cell cycle arrest in the S phase. Designing the single molecule that modulates multiple and specific targets, is paradigmin antitumor drug discovery. Here, we describe the synthesis, characterization, and in vitro antitumor activity of ruthenium(II)-arene complexes conjugated with 3-aminobenzamide derivatives, affecting poly(ADP-ribose) polymerase 1 enzymatic activity in vitro and interacting with DNA in human breast cancer cells. [Display omitted] •Poly(ADP-ribose) polymerase-1 (PARP-1) is a key player in repairing single-strand DNA breaks•Ru(II) arene complexes exhibit good efficiency in inhibiting PARP-1 activity.•Ru complexes exhibit good antiproliferative activity against breast cancer cells.•Ru(II) arene complexes display notable nuclear-targeting properties.•Ru(II) arene complexes interfere with the DNA replication.