Synthesis, chemical characterization, PARP inhibition, DNA binding and cellular uptake of novel ruthenium(II)-arene complexes bearing benzamide derivatives in human breast cancer cells
Authorized Users Only
2020
Authors
Pavlović, Marijana
Tadić, Ana
Gligorijević, Nevenka

Poljarević, Jelena

Petrović, Tamara G.

Dojčinović, Biljana

Savić, Aleksandar

Radulović, Siniša

Article (Published version)

Elsevier
Metadata
Show full item recordAbstract
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 cell...s 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.
Keywords:
Antitumor agents / Breast cancer / PARP inhibitor / Ruthenium(II)Source:
Journal of Inorganic Biochemistry, 2020, 210, 111155-Publisher:
- Elsevier
Projects:
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 451-03-68/2020-14/200168 (University of Belgrade, Faculty of Chemistry) (RS-200168)
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 451-03-68/2020-14/200043 (Institute of Oncology and Radiology of Serbia, Belgrade) (RS-200043)
Note:
- The peer-reviewed version: https://cer.ihtm.bg.ac.rs/handle/123456789/3713
DOI: 10.1016/j.jinorgbio.2020.111155
ISSN: 0162-0134
PubMed: 32768729