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

Publisher: Springer Country of Publication: Germany NLM ID: 9616326 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1327 (Electronic) Linking ISSN: 09498257 NLM ISO Abbreviation: J Biol Inorg Chem Subsets: MEDLINE

Original Publication: Berlin : Springer, c1996-

Angiogenesis Inhibitors/*pharmacology ; Antineoplastic Agents/*pharmacology ; DNA/*chemistry ; Neovascularization, Pathologic/*drug therapy ; Organoplatinum Compounds/*pharmacology ; Pyridines/*pharmacology; Angiogenesis Inhibitors/chemical synthesis ; Angiogenesis Inhibitors/chemistry ; Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Binding Sites/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Structure ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Organoplatinum Compounds/chemical synthesis ; Organoplatinum Compounds/chemistry ; Pyridines/chemistry ; Viscosity ; Zebrafish

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)(H 2 O)} 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)]Cl 2 ·2H 2 O (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.

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Keywords: Dinuclear platinum(II) complexes; Dual anticancer and anti-angiogenic activity; Minor groove covering

0 (Angiogenesis Inhibitors)
0 (Antineoplastic Agents)
0 (Ligands)
0 (Organoplatinum Compounds)
0 (Pyridines)
9007-49-2 (DNA)
91080-16-9 (calf thymus DNA)
NH9L3PP67S (pyridine)

Date Created: 20200313 Date Completed: 20210429 Latest Revision: 20210429

20221213

10.1007/s00775-020-01770-7

32162071