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 [(η 6 ‐arene)RuCl(Z)] + (Z = chelating ligand). Complexes [(η 6 ‐ p ‐cym)RuCl(NNO)](Cl) ( 2 ), [(η 6 ‐ p ‐cym)RuCl( L3 )](Cl) ( 3 ) and [(η 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 [(η 6 ‐ p ‐cym)RuCl 2 ] 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 m M 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)