Contrasting reactivity and cancer cell cytotoxicity of isoelectronic organometallic iridium(III) complexes.

Abstract

Replacing the N,N-chelating ligand 2,2'-bipyridine (bpy) in the Ir(III) pentamethylcyclopentadienyl (Cp*) complex [(η(5)-C(5)Me(5))Ir(bpy)Cl](+) (1) with the C,N-chelating ligand 2-phenylpyridine (phpy) to give [(η(5)-C(5)Me(5))Ir(phpy)Cl] (2) switches on cytotoxicity toward A2780 human ovarian cancer cells (IC(50) 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 [(η(5)-C(5)Me(5))Ir(phpy)(9-EtG-N7)]NO(3)·1.5CH(2)Cl(2) 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 NH(2) group (9-MeA) and carbons from phpy in the adenine adduct of complex 2. Calculations show that the most stable geometry of the adduct [(η(5)-C(5)Me(5))Ir(phpy)(9-EtG-N7)](+) (3b) has the C6O of 9-EtG orientated toward the pyridine ring of phpy, and for [(η(5)-C(5)Me(5))Ir(phpy)(9-MeA-N1)](+) (4(N1)a), the NH(2) 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.

• Authors: Zhe Liu, Luca Salassa, Abraha Habtemariam, Ana M Pizarro, Guy J Clarkson, Peter J Sadler
• Journal: Inorganic chemistry (Inorg Chem) Vol. 50 Issue 12 Pg. 5777-83 (Jun 20 2011) ISSN: 1520-510X [Electronic] United States
• PMID: 21618978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 American Chemical Society

Chemical References

• Antineoplastic Agents
• Ligands
• Organometallic Compounds
• Iridium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, 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, chemistry, pharmacology)
• Quantum Theory
• Stereoisomerism
• Structure-Activity Relationship