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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
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Abstract
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

WoS: 000564739400016

Scopus: 2-s2.0-85088982547
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URI
http://cer.ihtm.bg.ac.rs/handle/123456789/3634
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