Anticancer Activity and DNA Binding of a Bifunctional Ru(II) Arene Aqua-Complex with the 2,4-Diamino-6-(2-pyridyl)-1,3,5-triazine Ligand

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• 作者：Natalia Busto ; Jes煤s Valladolid ; Marta Mart铆nez-Alonso ; H茅ctor J. Lozano ; F茅lix A. Jal贸n ; Blanca R. Manzano ; A. M. Rodr铆guez ; M. Carmen Carri贸n ; Tarita Biver ; Jos茅 M. Leal ; Gustavo Espino ; Bego帽a Garc铆a
• 刊名：Inorganic Chemistry
• 出版年：2013
• 出版时间：September 3, 2013
• 年：2013
• 卷：52
• 期：17
• 页码：9962-9974
• 全文大小：590K
• 年卷期：v.52,no.17(September 3, 2013)
• ISSN：1520-510X

文摘

The synthesis and full characterization of the new aqua-complex [(畏⁶-p-cymene)Ru(OH₂)(魏²-N,N-2-pydaT)](BF₄)₂, [2](BF₄)₂, and the nucleobase derivative [(畏⁶-p-cymene)Ru(9-MeG)(魏²-N,N-2-pydaT)](BF₄)₂, [4](PF₆)₂, where 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine and 9-MeG = 9-methylguanine, are reported here. The crystal structures of both [4](PF₆)₂ and the chloro complex [(畏⁶-p-cymene)RuCl(魏²-N,N-2-pydaT)](PF₆), [1](PF₆), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(畏⁶-p-cymene)Ru(魏²-N,N-2-pydaT)]²⁺ and a simple model of DNA. NMR and kinetic absorbance studies have proven that the aqua-complex [2](BF₄)₂ binds to the N7 site of guanine in nucleobases, nucleotides, or DNA. A stable bifunctional interaction (covalent and partially intercalated) between the [(畏⁶-p-cymene)Ru(魏²-N,N-2-pydaT)]²⁺ fragment and CT-DNA has been corroborated by kinetic, circular dichroism, viscometry, and thermal denaturation experiments. The reaction mechanism entails the very fast formation of the Ru鈥揙-(PO₃) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru鈥揘7-(G) covalent bond is formed at the expense of the Ru鈥揙-(PO₃) bond, yielding a bifunctional complex. The dissociation rate of the intercalated fragment is slow, and this confers additional interest to [2](BF₄)₂ in view of the likely correlation between slow dissociation and biological activity, on the assumption that DNA is the only biotarget. Furthermore, [2](BF₄)₂ displays notable pH-dependent cytotoxic activity in human ovarian carcinoma cells (A2780, IC₅₀ = 11.0 渭M at pH = 7.4; IC₅₀ = 6.58 渭M at pH = 6.5). What is more, complex [2](BF₄)₂ is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and it shows moderate selectivity toward the cancer cell lines, in particular, A2780cis (IC₅₀ = 3.0 5 卤 0.08 渭M), relative to human lung fibroblast cells (MRC-5; IC₅₀ = 24 渭M), the model for healthy cells.