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

详细信息    查看全文

• 作者：Zhe Liu ; Luca Salassa ; Abraha Habtemariam ; Ana M. Pizarro ; Guy J. Clarkson ; Peter J. Sadler
• 刊名：Inorganic Chemistry
• 出版年：2011
• 出版时间：June 20, 2011
• 年：2011
• 卷：50
• 期：12
• 页码：5777-5783
• 全文大小：933K
• 年卷期：v.50,no.12(June 20, 2011)
• ISSN：1520-510X

文摘

Replacing the N,N-chelating ligand 2,2鈥?bipyridine (bpy) in the Ir^III pentamethylcyclopentadienyl (Cp*) complex [(畏⁵-C₅Me₅)Ir(bpy)Cl]⁺ (1) with the C,N-chelating ligand 2-phenylpyridine (phpy) to give [(畏⁵-C₅Me₅)Ir(phpy)Cl] (2) switches on cytotoxicity toward A2780 human ovarian cancer cells (IC₅₀ values of >100 渭M for 1 and 10.8 渭M for 2). Ir鈥揅l 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 [(畏⁵-C₅Me₅)Ir(phpy)(9-EtG-N7)]NO₃路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 [(畏⁵-C₅Me₅)Ir(phpy)(9-EtG-N7)]⁺ (3b) has the C6O of 9-EtG orientated toward the pyridine ring of phpy, and for [(畏⁵-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 鈭?.95, respectively. The strong nucleobase binding and high hydrophobicity of complex 2 probably contribute to its promising anticancer activity.