Novel C,N-chelate rhodium(III) and iridium(III) antitumor complexes incorporating a lipophilic steroidal conjugate and their interaction with DNA

• Published in: Dalton transactions : an international journal of inorganic chemistry 2012-11, Vol.41 (41), p.12847-12856
• Main Authors: Ruiz, José, Rodríguez, Venancio, Cutillas, Natalia, Samper, Katia G, Capdevila, Mercè, Palacios, Òscar, Espinosa, Arturo
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding, Competitive; Bonding strength; Cancer; Cathepsin B - antagonists & inhibitors; Cathepsin B - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Conjugates; Deoxyribonucleic acid; DNA - metabolism; Humans; Inhibitors; Iridium; Iridium - chemistry; Iridium - pharmacology; Levonorgestrel - chemistry; Levonorgestrel - pharmacology; Ligands; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Radio frequencies; Rhodium - chemistry; Rhodium - pharmacology
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c2dt31654d

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.