Tagging (Arene)ruthenium(II) Anticancer Complexes with Fluorescent Labels

Abstract

AbstractFluorescent (arene)ruthenium(II) complexes have been prepared by tagging a small fluorogenic reporter onto the chelating ligand of complexes of the type [(η6‐arene)RuCl(Z)]+ (Z = chelating ligand). Complexes [(η6‐p‐cym)RuCl(NNO)](Cl) (2), [(η6‐p‐cym)RuCl(L3)](Cl) (3) and [(η6‐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 [(η6‐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.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)