title: A potent ruthenium(II) antitumor complex bearing a lipophilic levonorgestrel group.
abstract: The novel steroidal conjugate 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(η(6)-p-cymene)(LEV-ppy)Cl] (2) have been prepared. At 48 h incubation time, complex 2 is more active than cisplatin (about 8-fold) in T47D (breast cancer) and also shows an improved efficiency when compared to its nonsteroidal analogue [Ru(η(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(II) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(II) complexes from the inactive components. The interaction of 2 with DNA was followed by electrophoretic mobility. Theoretical density functional theory calculations on complex 2 show the metal center far away from the lipophilic steroidal moiety and a labile Ru-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, thus forming a stronger Ru-N bond. We also found a minimum energy location for the chloride counteranion (4(+)·Cl(-)) inside the pseudocavity formed by the α side of the steroid moiety, the phenylpyridine chelating subsystem, and the guanine ligand, i.e., a host-guest species with a rich variety of nonbonding interactions that include nonclassical C-H···anion bonds, as supported by electrospray ionization mass spectra.
authors.affiliation: Departamento de Química Inorgánica, Universidad de Murcia, 30071, Murcia, Spain. jruiz@um.es
authors.forename: José
authors.initials: J
authors.lastname: Ruiz
authors.forename: Venancio
authors.initials: V
authors.lastname: Rodríguez
authors.forename: Natalia
authors.initials: N
authors.lastname: Cutillas
authors.forename: Arturo
authors.initials: A
authors.lastname: Espinosa
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hannon
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D016912:Levonorgestrel / Q000737:chemistry*; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012428:Ruthenium / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016912:Levonorgestrel; D006147:Guanine; D012428:Ruthenium; C014542:9-ethylguanine