Contrasting Reactivity and Cancer Cell Cytotoxicity of Isoelectronic Organometallic Iridium(III) Complexes

• Published in: Inorganic chemistry Vol. 50; no. 12; pp. 5777 - 5783
• Main Authors: Liu, Zhe, Salassa, Luca, Habtemariam, Abraha, Pizarro, Ana M, Clarkson, Guy J, Sadler, Peter J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20.06.2011
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Iridium - chemistry; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Quantum Theory; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0020-1669; 1520-510X; 1520-510X
• DOI: 10.1021/ic200607j

Replacing the N,N-chelating ligand 2,2′-bipyridine (bpy) in the IrIII pentamethylcyclopentadienyl (Cp*) complex [(η5-C5Me5)Ir(bpy)Cl]+ (1) with the C,N-chelating ligand 2-phenylpyridine (phpy) to give [(η5-C5Me5)Ir(phpy)Cl] (2) switches on cytotoxicity toward A2780 human ovarian cancer cells (IC50 values of >100 μM for 1 and 10.8 μM for 2). Ir–Cl hydrolysis is rapid for both complexes (hydrolysis equilibrium reached in <5 min at 278 K). Complex 2 forms adducts with both 9-ethylguanine (9-EtG) and 9-methyladenine (9-MeA), but preferentially with 9-EtG when in competition (ca. 85% of total Ir after 24 h). The X-ray crystal structure of [(η5-C5Me5)Ir(phpy)(9-EtG-N7)]NO3·1.5CH2Cl2 confirms N7 binding to guanine. Two-dimensional NMR spectra show that complex 2 binds to adenine mainly through N1, consistent with density functional theory (DFT) calculations. DFT calculations indicate an interaction between the nitrogen of the NH2 group (9-MeA) and carbons from phpy in the adenine adduct of complex 2. Calculations show that the most stable geometry of the adduct [(η5-C5Me5)Ir(phpy)(9-EtG-N7)]+ (3b) has the C6O of 9-EtG orientated toward the pyridine ring of phpy, and for [(η5-C5Me5)Ir(phpy)(9-MeA-N1)]+ (4(N1) a), the NH2 group of 9-EtA is adjacent to the phenyl ring side of phpy. Complex 2 is more hydrophobic than complex 1, with log P values of 1.57 and −0.95, respectively. The strong nucleobase binding and high hydrophobicity of complex 2 probably contribute to its promising anticancer activity.