Preparation of Organometallic Ruthenium–Arene–Diaminotriazine Complexes as Binding Agents to DNA

Abstract

The reactions of two diaminotriazine ligands 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine (2-pydaT) and 6-phenyl-2,4-diamino-1,3,5-triazine (PhdaT) with ruthenium-arene precursors led to a new family of ruthenium(II) compounds that were spectroscopically characterized. Four of the complexes were cationic, with the general formula [(η(6)-arene)Ru(κ(2)-N,N-2-pydaT)Cl]X (X=BF(4), TsO; arene=p-cymene: 1·BF(4), 1·TsO; arene=benzene: 2·BF(4), 2·TsO). The neutral cyclometalated complex [(η(6)-p-cymene)Ru(κ(2)-C,N-PhdaT*)Cl] (3) was also isolated. The structures of complexes 2·BF(4) and 3·H(2)O were determined by X-ray diffraction. Complex 1·BF(4) underwent a partial reversible-aquation process in water. UV/Vis and NMR spectroscopic measurements showed that the reaction was hindered by the addition of NaCl and was pH-controlled in acidic solution. At pH 7.0 (sodium cacodylate) Ru-Cl complex 1·BF(4) was the only species present in solution, even at low ionic strength. However, in alkaline medium (KOH), complex 1·BF(4) underwent basic hydrolysis to afford a Ru-OH complex (5). Fluorimetric studies revealed that the interaction of complex 1·BF(4) with DNA was not straightforward; instead, its main features were closely linked to ionic strength and to the [DNA]/complex ratio. The bifunctional complex 1·BF(4) was capable of interacting concurrently through both its p-cymene and 2-pydaT groups. Cytotoxicity and genotoxicity studies showed that, contrary to the expected behavior, the complex species was biologically inactive; the formation of a Ru-OH complex could be responsible for such behavior.

Alteration of steric hindrance modulates glutathione resistance and cytotoxicity of three structurally related RuII-p-cymene complexes

“…The similarity in the DNA binding constants for the 12 h hydrolyzed sample and the fresh solution of complexes may be attributed to the slow hydrolysis, since the timescale of the DNA binding experiment is smaller (1.5 h). The p-cymene complexes of Ru II show similar binding constants with DNA as reported by Garcia et al [47][48][49][50] Aquation is thought to be a major step which may be involved in activation of this type of metal complex. However, extracellular aquation may prevent the internalization of the complexes due to their di-positive charge and higher hydrophilicity.…”

Monomer–Dimer Divergent Behavior toward DNA in a Half-Sandwich Ruthenium(II) Aqua Complex. Antiproliferative Biphasic Activity

“…1 We have assessed recently the cytotoxic activity of ruthenium(II) arene chlorido complexes with 2-aryldiazole ligands, 2 establishing structure− activity relationships, and reported on the synthesis and anticancer properties of other families of bifunctional Ru(II) arene complexes with 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine (2-pydaT) and phenanthroline ligands, verifying that the formation of bifunctional complexes strongly relies on the structure of both the complex and the aromatic ancillary ligand, whereas intercalation of the arene group (p-cymene or benzene) was not observed. 3 None of the complexes investigated so far have shown deviation from the Lambert law that could suggest aggregation in aqueous solution. Aggregation in nonaqueous solution has been reported for amino-acidate half-sandwich ruthenium(II) complexes 4 and cationic half-sandwich Ru(II) complexes bearing neutral N,O-ligands.…”

Selected Pharmacological Applications of 1<sup>st</sup> Row Transition Metal Complexes: A review

“…In fact, these smart features have fuelled the complexes to be used in a broad spectrum of applications, from fluorescent markers to DNA footprinting agents, to electrochemical probes [34]. Among the metal ions regarded as coordination centers of potential anticancer agents, platinum and ruthenium ions are commonly explored [35][36][37]. However, there is an emerging curiosity in the synthesis of cheaper first-row coordination compounds as efficient DNA binders with potential cytotoxic activity [38][39][40][41][42].…”