title: 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.
abstract: The synthesis and full characterization of the new aqua-complex [(η(6)-p-cymene)Ru(OH2)(κ(2)-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(η(6)-p-cymene)Ru(9-MeG)(κ(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 [(η(6)-p-cymene)RuCl(κ(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 [(η(6)-p-cymene)Ru(κ(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 [(η(6)-p-cymene)Ru(κ(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-O-(PO3) 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-O-(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 μM at pH = 7.4; IC50 = 6.58 μM 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 ± 0.08 μM), relative to human lung fibroblast cells (MRC-5; IC50 = 24 μM), the model for healthy cells.
authors: Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s.n., 09001, Burgos, Spain.
authors: Natalia
authors: N
authors: Busto
authors: Jesús
authors: J
authors: Valladolid
authors: Marta
authors: M
authors: Martínez-Alonso
authors: Héctor J
authors: HJ
authors: Lozano
authors: Félix A
authors: FA
authors: Jalón
authors: Blanca R
authors: BR
authors: Manzano
authors: A M
authors: AM
authors: Rodríguez
authors: M Carmen
authors: MC
authors: Carrión
authors: Tarita
authors: T
authors: Biver
authors: José M
authors: JM
authors: Leal
authors: Gustavo
authors: G
authors: Espino
authors: Begoña
authors: B
authors: García
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D000081007:Cymenes; D004247:DNA / Q000378:metabolism*; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D012428:Ruthenium / Q000737:chemistry* / Q000494:pharmacology; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000081007:Cymenes; D007364:Intercalating Agents; D039821:Monoterpenes; D014227:Triazines; C007210:4-cymene; D012428:Ruthenium; D004247:DNA