title: Novel C,N-chelate rhodium(III) and iridium(III) antitumor complexes incorporating a lipophilic steroidal conjugate and their interaction with DNA.
abstract: The novel steroidal conjugates [M(η(5)-C(5)Me(5))Cl(LEV-ppy)] (M = Rh (1) and Ir (2)) bearing the lipophilic levonorgestrel group 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy), where the chelating ligand is N and C-bound, have been prepared and characterized. Both compounds are more active than cisplatin (about 6-fold) in T47D (breast cancer) at 48 h incubation time. On the other hand, very low resistance factors (RF) of 1 and 2 in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF = 0.9 and 1.1, respectively). The iridium steroidal compound 2 is twice as active as the non-steroidal analogue 2', whose promising anticancer activity has recently been reported by Sadler. Theoretical DFT calculations on complexes 1 and 2 at the B3LYP-D/def2-TZVP-ecp level of theory show that the strongest bond to the metal atom is the η(5)-interaction to the Cp* ligand and that both of them feature a rather strong metal-chlorine bond. The new steroidal conjugates 1 and 2 are able to bind to DNA according to Hoechst 33258 displacement experiments and ESI-TOF MS spectrometry studies. Complexes 1 and 2 are also cathepsin B inhibitors, an enzyme implicated in a number of cancer related events.
authors.affiliation: Departamento de Química Inorgánica and Regional Campus of International Excellence Campus Mare Nostrum, Universidad de Murcia and Instituto Murciano de Investigación Biosanitaria, 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: Katia G
authors.initials: KG
authors.lastname: Samper
authors.forename: Mercè
authors.initials: M
authors.lastname: Capdevila
authors.forename: Òscar
authors.initials: Ò
authors.lastname: Palacios
authors.forename: Arturo
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D006801:Humans; D007495:Iridium / Q000737:chemistry* / Q000494:pharmacology; D016912:Levonorgestrel / Q000737:chemistry* / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D012238:Rhodium / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D007495:Iridium; D016912:Levonorgestrel; D004247:DNA; D012238:Rhodium; D002401:Cathepsin B