10.1021/ic8020222.s002
Sabine H. van Rijt
Sabine
H. van Rijt
Anna F. A. Peacock
Anna
F. A. Peacock
Russell D. L. Johnstone
Russell
D. L. Johnstone
Simon Parsons
Simon
Parsons
Peter J. Sadler
Peter J.
Sadler
Organometallic Osmium(II) Arene Anticancer Complexes Containing Picolinate Derivatives
American Chemical Society
2009
cisplatin resistance
hydrolysis rates
2H
IC 50 values
OH
cancer cell cytotoxicity
para carboxylate substituent
25 μ M
cell lines
cell line
steric effects
HCT 116
complexes 4
nucleobase binding
para substituents
aqua adducts 3
6 show
4.4 h
CO
HCT 116 colon cancer cells
288 K
chelating ligand
chemical reactivity
cytotoxicity assays
osmium arene complexes
pKa values
9 EtG
9 EtA
2009-02-16 00:00:00
Dataset
https://acs.figshare.com/articles/dataset/Organometallic_Osmium_II_Arene_Anticancer_Complexes_Containing_Picolinate_Derivatives/2878375
Chlorido osmium(II) arene [(η<sup>6</sup>-biphenyl)Os<sup>II</sup>(X-pico)Cl] complexes containing X = Br (<b>1</b>), OH (<b>2</b>), and Me (<b>3</b>) as <i>ortho</i>, or X = Cl (<b>4</b>), CO<sub>2</sub>H (<b>5</b>), and Me (<b>6</b>) as <i>para</i> substituents on the picolinate (pico) ring have been synthesized and characterized. The X-ray crystal structures of <b>1</b> and <b>6</b> show typical “piano-stool” geometry with intermolecular π-π stacking of the biphenyl outer rings of <b>6</b>. At 288 K the hydrolysis rates follow the order <b>2</b> ≫ <b>6</b> > <b>4</b> > <b>3</b> > <b>5</b> ≫ <b>1</b> with half-lives ranging from minutes to 4.4 h illustrating the influence of both electronic and steric effects of the substituents. The p<i>K</i><sub>a</sub> values of the aqua adducts <b>3A</b>, <b>4A</b>, <b>5A</b>, and <b>6A</b> were all in the range of 6.3−6.6. The <i>para</i>-substituted pico complexes <b>4</b>−<b>6</b> readily formed adducts with both 9-ethyl guanine (9EtG) and 9-ethyl adenine (9EtA), but these were less favored for the <i>ortho</i>-substituted complexes <b>1</b> and <b>3</b> showing little reaction with 9EtG and 9EtA, respectively. Density-functional theory calculations confirmed the observed preferences for nucleobase binding for complex <b>1</b>. In cytotoxicity assays with A2780, cisplatin-resistant A2780cis human ovarian, A549 human lung, and HCT116 colon cancer cells, only complexes <b>4</b> (<i>p</i>-Cl) and <b>6</b> (<i>p</i>-Me) exhibited significant activity (IC<sub>50</sub> values < 25 μM). 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 <b>5</b> is attributed to the negative charge on its <i>para</i> 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.