New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities

Autor:	Marija D. Živković, Aleksandar Pavic, Ivana S. Đorđević, Andjela A. Franich, Goran V. Janjić, Tatjana Ilic-Tomic, Jasmina Nikodinovic-Runic, Snežana Rajković
Rok vydání:	2020
Předmět:	Minor groove covering Organoplatinum Compounds Pyridines Stereochemistry Cell chemistry.chemical_element Angiogenesis Inhibitors Antineoplastic Agents Ligands 010402 general chemistry 01 natural sciences Biochemistry Adduct Inorganic Chemistry chemistry.chemical_compound Bipyridine Dual anticancer and anti-angiogenic activity In vivo Cell Line Tumor Pyridine medicine Animals Humans Zebrafish Cell Proliferation Binding Sites Dose-Response Relationship Drug Molecular Structure Neovascularization Pathologic Viscosity 010405 organic chemistry DNA Neoplasms Experimental Sunitinib malate 0104 chemical sciences 3. Good health Molecular Docking Simulation medicine.anatomical_structure chemistry Dinuclear platinum(II) complexes Drug Screening Assays Antitumor Platinum
Zdroj:	Journal of Biological Inorganic Chemistry
ISSN:	1432-1327 0949-8257
DOI:	10.1007/s00775-020-01770-7
Popis:	New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl}2(μ-L)]2+ complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H2O)}2(μ-L)]4+, interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl}2(μ-4,4′-bipy)]Cl2·2H2O (4,4′-bipy is 4,4′-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish–mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs.
Databáze:	OpenAIRE
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