Derivation of Structure鈥揂ctivity Relationships from the Anticancer Properties of Ruthenium(II) Arene Complexes with 2-Aryldiazole Ligands

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• 作者：Marta Mart铆nez-Alonso ; Natalia Busto ; F茅lix A. Jal贸n ; Blanca R. Manzano ; Jos茅 M. Leal ; Ana M. Rodr铆guez ; Bego帽a Garc铆a ; Gustavo Espino
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：October 20, 2014
• 年：2014
• 卷：53
• 期：20
• 页码：11274-11288
• 全文大小：777K
• ISSN：1520-510X

文摘

The ligands 2-pyridin-2-yl-1H-benzimidazole (HL¹), 1-methyl-2-pyridin-2-ylbenzimidazole (HL²), and 2-(1H-imidazol-2-yl)pyridine (HL³) and the proligand 2-phenyl-1H-benzimidazole (HL⁴) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(畏⁶-arene)RuCl(魏²-N,N-HL)]Y [HL = HL¹, HL², or HL³; Y = Cl or BF₄; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(畏⁶-arene)Ru(OH₂)(魏²-N,N-HL¹)](Y)₂ (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(畏⁶-arene)Ru(9-MeG)(魏²-N,N-HL¹)](PF₆)₂ (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(畏⁶-arene)RuCl(魏²-N,N-L¹)] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(畏⁶-p-cym)RuCl(魏²-N,C-L⁴)]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure鈥揳ctivity relationships. Three of the compounds with the general formula [(畏⁶-arene)RuCl(魏²-N,N-HL¹)]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity.