Journal
INORGANIC CHEMISTRY
Volume 52, Issue 17, Pages 9962-9974Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ic401197a
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Funding
- Spanish MICINN [CTQ2011-24434, CTQ2009-1305I/BQU]
- FEDER
- Junta de Castilla y Leon (Fondo Social Europe) [BU-299Al2-1]
- Obra Social la Caixa
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The synthesis and full characterization of the new aqua-complex [('76-p-cymene)Ru(OH2)(x2-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(?76-p-cymene)Ru(9 MeG)(K2-N,N-2-pydaT)KBF4)2, [4](PF6)2, where 2-pydaT = 2,4diamino-6-(2-pyridy1)-1,3,5-triazine and 9-MeG 9-methylguanine, are reported here. The crystal structure's of both [4](PF6)2 nd the chloro complex [(q6-p-cymene)RuCI(K2-N,N-2-pydaT(PF6), (P6), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(,76-p-c-ymene)Ru(K2-N,N-2-pyclaT)]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 [(//6-p-cymene)Ru(x2-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-0-(P03) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru.N7(G) covalent bond is formed at the expense of the Ru-0 (P03) 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 carcinoli'm cells (A2780, IC50 = 11.0 pM at pH = 7.4; ICso = 6.58 pM at pH = 6.5). 'What is more, complex [2](EtF4.)2 is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and dshows moderate selectivity toward the cancer cell lines, in particular, A2780cis (ICso = 3.0 5 + 0.08 HM), relative tohuman lung fibroblast cells (MRC-S; ICso = 24 pM), the model for healthy cells.
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