Organometallic Osmium(II) Arene Anticancer Complexes Containing Picolinate Derivatives

Abstract

Chlorido osmium(II) arene [(eta(6)-biphenyl)Os(II)(X-pico)Cl] complexes containing X = Br (1), OH (2), and Me (3) as ortho, or X = Cl (4), CO(2)H (5), and Me (6) as para substituents on the picolinate (pico) ring have been synthesized and characterized. The X-ray crystal structures of 1 and 6 show typical "piano-stool" geometry with intermolecular pi-pi stacking of the biphenyl outer rings of 6. At 288 K the hydrolysis rates follow the order 2 >> 6 > 4 > 3 > 5 >> 1 with half-lives ranging from minutes to 4.4 h illustrating the influence of both electronic and steric effects of the substituents. The pK(a) values of the aqua adducts 3A, 4A, 5A, and 6A were all in the range of 6.3-6.6. The para-substituted pico complexes 4-6 readily formed adducts with both 9-ethyl guanine (9EtG) and 9-ethyl adenine (9EtA), but these were less favored for the ortho-substituted complexes 1 and 3 showing little reaction with 9EtG and 9EtA, respectively. Density-functional theory calculations confirmed the observed preferences for nucleobase binding for complex 1. In cytotoxicity assays with A2780, cisplatin-resistant A2780cis human ovarian, A549 human lung, and HCT116 colon cancer cells, only complexes 4 (p-Cl) and 6 (p-Me) exhibited significant activity (IC(50) values < 25 microM). Both of these complexes were as active as cisplatin in A2780 (ovarian) and HCT116 (colon) cell lines, and even overcome cisplatin resistance in the A2780cis (ovarian) cell line. The inactivity of 5 is attributed to the negative charge on its para carboxylate substituent. These data illustrate how the chemical reactivity and cancer cell cytotoxicity of osmium arene complexes can be controlled and "fine-tuned" by the use of steric and electronic effects of substituents on a chelating ligand to give osmium(II) arene complexes which are as active as cisplatin but have a different mechanism of action.

Designing organometallic compounds for catalysis and therapy

“…The effect of substituents on the pyridyl ring has been explored for Os II arene anticancer complexes containing picolinate derivatives (R-pico) as chelating ligand and has led to the identification of structure -activity relationships. 145 The rates of hydrolysis at 288 K of derivatives of [(η 6 -biphenyl)Os II (R-pico)Cl] (81) decrease with decreasing electron-donor strength of the substituent OH > Me > Br > COO -( Figure 33). In this series, a para carboxylate proved to be the most deactivating substituent, slowing the hydrolysis down the most.…”

Functionalization of Osmium Arene Anticancer Complexes with (Poly)arginine: Effect on Cellular Uptake, Internalization, and Cytotoxicity

“…Parent complex 1, ([(η 6 -bip)Os(picolinate)Cl]), and precursor complex 2, ([(η 6 -bip)Os(4-CO 2 -picolinate)Cl]), were synthesized and characterized as previously described (19). Solid-phase bound and protected arginine derivatives were purchased from Fluka, reaction syringes (5 mL) were bought from Multisyntech (Witten, Germany).…”

“…An interesting method for the delivery of therapeutics to the cell nucleus has been described by Metzler-Nolte et al (13). Recently we and others have reported organometallic osmium(II) arene complexes with promising cancer cell cytotoxicity (14)(15)(16)(17)(18)(19)(20)(21). Some of these complexes have been shown to induce non-repairable damage to DNA by causing a large degree of DNA unwinding (22).…”

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

“…100 mM), the pyridylphosphinate complexes remains intact as the chloride adduct, but at lower intracellular chloride concentration (approx. 20 mM in cytoplasm) 25 significant amounts of the aqua adduct are present. With this in mind, we sought to measure the pK a of the bound water molecule and to establish how the pK a varies with the H-NMR spectra (D2O : CD3OD 9:1, 298 K, 400 MHz) of (A) complex 1 and 1a at approximately 1:1 equilibrium ratio, (B) chloride complex 1, following addition of 100 mM NaCl and (C) aqua complex 1a, following addition of AgNO3 and filtration of AgCl.…”