Novel "ruthenium cyclopentadienyl"-peptide conjugate complexes against human FGFR(+) breast cancer.

In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh)(2,2'-bipy)][CFSO] (where Cp = η-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 η-cyclopentadienyl were synthesized, namely [Ru(η-CHCOOH)(2,2'-bipy)(PPh)][CFSO] (TM281) and its precursors, [Ru(η-CHCOOCHCH)(η-2,2'-bipy)(PPh)][CFSO] (3) and [Ru(η-CHCOOCHCH)(PPh)Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η-cyclopentadienyl ligand of complex 3 with KCO 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.