New Water-Soluble Ruthenium(II) Terpyridine Complexes for Anticancer Activity: Synthesis, Characterization, Activation Kinetics, and Interaction with Guanine Derivatives

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• 作者：Ana Rilak ; Ioannis Bratsos ; Ennio Zangrando ; Jakob Kljun ; Iztok Turel ; 沤ivadin D. Bugar膷i膰 ; Enzo Alessio
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：June 16, 2014
• 年：2014
• 卷：53
• 期：12
• 页码：6113-6126
• 全文大小：538K
• 年卷期：v.53,no.12(June 16, 2014)
• ISSN：1520-510X

文摘

With the aim of assessing whether ruthenium(II) compounds with meridional geometry might be utilized as potential antitumor agents, a series of new, water-soluble, monofunctional ruthenium(II) complexes of the general formula mer-[Ru(L₃)(N-N)X][Y]_n (where L₃ = 2,2鈥?6鈥?2鈥?terpyridine (tpy) or 4鈥?chloro-2,2鈥?6鈥?2鈥?terpyridine (Cl-tpy), N-N = 1,2-diaminoethane (en), 1,2-diaminocyclohexane (dach), or 2,2鈥?bipyridine (bpy); X = Cl or dmso-S; Y = Cl, PF₆, or CF₃SO₃; n = 1 or 2, depending on the nature of X) were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and for three of them, i.e., [Ru(Cl-tpy)(bpy)Cl][Cl] (3_Cl), [Ru(Cl-tpy)(en)(dmso-S)][Y]₂ [Y = PF₆ (6_PF6), CF₃SO₃ (6_OTf)] and [Ru(Cl-tpy)(bpy)(dmso-S)][CF₃SO₃]₂ (8_OTf), the X-ray structure was also determined. The new terpyridine complexes, with the exception of 8, are well soluble in water (>25 mg/mL). ¹H and ³¹P NMR spectroscopy studies performed on the three selected complexes [Ru(Cl-tpy)(N-N)Cl]⁺ [N-N = en (1), dach (2), and bpy (3)] demonstrated that, after hydrolysis of the Cl ligand, they are capable of interacting with guanine derivatives [i.e., 9-methylguanine (9MeG) or guanosine-5鈥?monophosphate (5鈥?GMP)] through N7, forming monofunctional adducts with rates and extents that depend strongly on the nature of N-N: 1 鈮?2 3. In addition, compound 1 shows high selectivity toward 5鈥?GMP compared to adenosine-5鈥?monophosphate (5鈥?AMP), in a competition experiment. Quantitative kinetic investigations on 1 and 2 were performed by means of UV/visible spectroscopy. Overall, the complexes with bidentate aliphatic diamines proved to be superior to those with bpy in terms of solubility and reactivity (i.e., release of Cl^{鈥?/sup> and capability to bind guanine derivatives). Contrary to the chlorido compounds, the corresponding dmso derivatives proved to be inert (viz., they do not release the monodentate ligand) in aqueous media.}