Tagging (Arene)ruthenium(II) anticancer complexes with fluorescent labels

Fluorescent (arene)ruthenium(II) complexes have been prepared by tagging a small fluorogenic reporter onto the chelating ligand of complexes of the type [(eta(6)-arene)RuCl(Z)](+) (Z = chelating ligand). Complexes [(eta(6)-p-cym)RuCl(NNO)](Cl) (2), [(eta(3)-p-cym)RuCl(L3)](Cl) (3) and [(eta(6)-p- cym)RuCl(L4)](Cl) (4) {p-cym = p-cymene, NNO = 2-[(2-aminoethyl)amino]ethanol, L3 = 2-[(2-aminoethyl)amino]ethyl-2-(methylamino)benzoate and L4 = N-{2-[(2-aminoethyl)amino]ethyl}-2-(methylamino)benzamide} were obtained in good yield from the reaction of the Ru dimer [(eta(6)-p-cym)- RuCl2](2) (1) and the corresponding ligand. The compounds have been fully characterized and their X-ray crystal structures are reported. Compounds 3 and 4 show a photoluminescence response centered at 435 nm with partial fluorescence quenching of the fluorogenic reporters L3 and L4 upon coordination to the metal center. Species 2-4 show good solubility both in water and organic solvents. In water, 2-4 readily hydrolyze to form the aqua complexes. These are stable at acidic pH forming 10-15 % of the corresponding hydroxido complexes in buffered solution (25 mm HEPES) as the pH is raised to a physiological value (pH = 7.44). Under these conditions, 4 (but not 2 or 3) undergoes a fast pH-dependent reversible intramolecular rearrangement. Experimental data and semiempirical calculations indicate that the major species arising from this transformation is a complex with a tridentate chelating ligand following deprotonation at the nitrogen atom of the amide group. Esterase-catalyzed hydrolysis of 3 liberates isatoic acid (MIAH) and generates 2 indicating that the complex is a substrate for the enzyme. Complexes similar to 3 may have potential for esterase-activated Ru-based prodrug delivery systems. (c) Wiley-VCH Verlag GmbH & Co. KGdA, 69451 Weinheim, Germany, 2007.