Platinum() complexes showing high cytotoxicity toward A2780 ovarian carcinoma cells

• Published in: Dalton transactions : an international journal of inorganic chemistry Vol. 48; no. 34; pp. 1381 - 1393
• Main Authors: Choroba, Katarzyna, Machura, Barbara, Raposo, Luis R, Ma ecki, Jan G, Kula, Slawomir, Paj k, Micha, Erfurt, Karol, Maro, Anna M, Fernandes, Alexandra R
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 14.09.2019
• Subjects: Absorption spectra; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Aromatic compounds; Biotechnology; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Chemical analysis; Colon; Constitution; Coordination compounds; Crystallography; Cytotoxicity; Depolarization; Drug Screening Assays, Antitumor; Electrochemistry; Emission spectra; Female; Fibroblasts; Humans; Hydrogen bonds; Mathematical analysis; Mitochondria; Models, Molecular; Molecular Conformation; Molecular orbitals; NMR spectroscopy; Nuclei; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Ovarian Neoplasms - pathology; Pyridines; Reactive Oxygen Species - metabolism; Substitutes; Toxicity; Transition metals; X ray analysis
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c9dt02894c

2,6-Bis(thiazol-2-yl)pyridines functionalized with 9-anthryl ( L 1 ), 9-phenanthryl ( L 2 ), and 1-pyrenyl ( L 3 ) groups were used for the preparation of [Pt(L n )Cl]CF 3 SO 3 ( 1-3 ). The constitution of the Pt( ii ) complexes was determined by 1 H and 13 C NMR spectroscopy, HR-MS spectrometry, elemental analysis and X-ray analysis (for ( 1 )). The electrochemical and photophysical properties of [Pt(L n )Cl]CF 3 SO 3 were compared with the behaviour of the Pt( ii ) complexes with aryl-substituted 2,2′:6′,2′′-terpyridine ligands. What is noteworthy is that the coordination ability of dtpy toward the Pt( ii ) centre was investigated for the first time. All complexes were tested in vitro by MTS assay on four tumor cell lines, A2780 (ovarian carcinoma), HTC116 (colon rectal carcinoma), MCF7 (breast adenocarcinoma), and PC3 (prostate carcinoma) and on normal primary fibroblasts. Compounds ( 1-3 ) showed a dose dependent antiproliferative effect in the A2780 cell line with ( 3 ) > ( 2 ) > ( 1 ) and this loss of A2780 cell viability was due to a combination of an apoptotic cell death mechanism via mitochondria and autophagic cell death. Exposure to IC 50 concentration of ( 2 ) induced an increase in the number of apoptotic nuclei and a depolarization of the mitochondrial membrane which is consistent with the induction of apoptosis while exposure to IC 50 concentration of ( 3 ) showed an increase in the apoptotic nuclei with a slight hyperpolarization of the mitochondrial membrane that might indicate an initial step of apoptosis induction. The complexes ( 2 ) and ( 3 ) induce an increase in the production of intracellular ROS which is associated with the trigger of the apoptotic pathways. The ROS production was augmented by the presence of oxidants and correlated with an increase of oxygen radicals. The IC 50 of ( 2 ) and ( 3 ) (4.4 μM and 2.9 μM, respectively) was similar to the IC 50 of cisplatin (3.4 μM) in the A2780 cell line, which together with their low cytotoxicity in normal fibroblasts, demonstrates their potential for further studies. 2,6-Bis(thiazol-2-yl)pyridines functionalized with 9-anthryl ( L 1 ), 9-phenanthryl ( L 2 ), and 1-pyrenyl ( L 3 ) groups were used for the preparation of [Pt(L n )Cl]CF 3 SO 3 ( 1-3 ) with high cytotoxic activity against ovarian cancer cells.