João Franco Machado, Miguel Machuqueiro, Fernanda Marques, M. Paula Robalo, M. Fátima M. Piedade, M. Helena Garcia, João D. G. Correia, and Tânia S. Morais
In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh3)(2,2′-bipy)][CF3SO3] (where Cp = η5-cyclopentadienyl) TM34 towards FGFR(+) breast cancer cells. Molecular dynamics (MD) simulations of TM34 in a phosphatidylcholine membrane model pinpointed the cyclopentadienyl group as a favorable derivatization position for the peptide conjugation approach. Three new Ru(II) complexes presenting a functionalized η5-cyclopentadienyl were synthesized, namely [Ru(η5-C5H4COOH)(2,2′-bipy)(PPh3)][CF3SO3] (TM281) and its precursors, [Ru(η5-C5H4COOCH2CH3)(η2-2,2′-bipy)(PPh3)][CF3SO3] (3) and [Ru(η5-C5H4COOCH2CH3)(PPh3)2Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η5-cyclopentadienyl ligand of complex 3 with K2CO3 in water/acetonitrile, followed by mild protonation using an ion exchange resin. The newly synthesized complexes were fully characterized by NMR, FTIR and UV-vis spectroscopic techniques. Also, electrochemical studies were carried out by means of cyclic voltammetry in order to evaluate the stability of the compounds. Single crystal X-ray diffraction studies were carried out for compounds 3 and TM281 which crystallized in the monoclinic system, space group P21/n. The unprecedented synthesis and characterization of three half-sandwich ruthenium(II)-cyclopentadienyl peptide conjugates and their preliminary biological evaluation against human FGFR(+) and FGFR(−) breast cancer cells are also reported.