1. Ferrocene-functionalised Multinuclear
Organometallic Anticancer Compounds with
Ir, Rh, Ru, and Os Co-centres
Kelvin Tong,a Mario Kubanik,a Muhammad Hanif,a Stephen Jamieson,b Christian Hartingera
E-mail: kton030@aucklanduni.ac.nz
aSchool of Chemical Sciences, The University of Auckland, Private Bag 92019 Auckland 1142, New Zealand
bAuckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019 Auckland 1142, New Zealand
Ruthenium-based Anticancer Drugs
The discovery of cisplatin in the 20th century has revolutionised the field of
metal based anticancer drug and cancer chemotherapy. While seeking for
potential successors, the properties of ruthenium(II) arene complexes
have attracted much attentions. The characteristic piano-stool geometry is
promising as it enables the compound to be tuned according to our
“flavours”.
• R = The aromatic “seat” that provides lipophilicity
to bring the complex across cell membranes
easily.
• X = usually a halogen leaving group
• Y and Z = can be bioactive ligands that
coordinate to the Ru(II) centre in either mono- or
bidentate fashion.
Synthetic Chemistry
Series 1 M Ar X Series 2 M Ar X
1a Ru Cym Cl 2a Ru Cym Cl
1b Ru Cym Br 2b Ru Cym Br
1c Ru Cym I 2c Ru Cym I
1d Os Cym Cl 2d Os Cym Cl
1e Os Cym I 2e Os Cym I
1f Ru Biph Cl 2f Rh Cp* Cl
1g Os Biph Cl 2g Ir Cp* Cl
1h Rh Cp* Cl
1i Ir Cp* Cl
Firstly, ferrocene is coupled with the bioactive ligand using different
coupling reagents. Followed by reacting the desired metal dimer with the
ferrocenyl ligand in which its Y and Z coordination sites can coordinate to
the metal in a bidentate manner.
Why Multinuclear Metal Complexes?
Biological Studies
Introducing multiple metal centres to a complex can potentially enhance its
pharmacological properties and broaden its spectrum of bioactivity. This
means a single compound can offer multiple pathways to fight tumour
cells. Therefore, this can overcome the persisting issue of drug resistance
in cancer cells, making chemotherapies more effective.
Why To Choose Ferrocene?
Under strong oxidising conditions, the cytotoxic ferrocenium cation is
formed which aids killing cancer cells. There have been various attempts in
introducing ferrocene into different anticancer compounds and many have
shown improved activity.
To date, 1 ligand and 7 corresponding complexes have been evaluated in
cancer cell lines such as HCT116 (human colorectal carcinoma), H460
(human large cell lung carcinoma) and SiHa (human cervix carcinoma).
It appears that the Ru(II)-cymene complexes 1a-c have better
antiproliferative activity compared to the osmium analogues as indicated by
their low IC50 values (concentration needed to reduce cancer cell growth by
50%). In particular, they are most active in the HCT116 cell line.
Compound HCT116 H460 SiHa
Ligand 1 >64 >64 >64
1a 10.79 ± 6.13 15.22 ± 4.35 19.61 ± 9.33
1b 16.94 ± 2.24 22.47 ± 5.43 18.79 ± 2.36
1c 8.65 ± 1.26 16.01 ± 1.14 14.26 ± 1.44
1d 17.61 ± 11.59 35.42 ± 25.28 26.98 ± 13.12
1e 12.59 ± 2.14 27.42 ± 4.71 23.01 ± 5.03
1f 20.35 ± 6.25 28.86 ± 2.20 23.24 ± 0.87
1g 33.86 ± 2.52 >30 36.86 ± 2.36
IC50(μM) of selected complexes
Aqueous Stability
Conclusions and Future Work
References and Acknowledgements
Top, S. et al., Chemistry-A European Journal. 2003, 21, 5223-5236
Ang, W. et al., Journal of Organometallic Chemistry. 2011, 5, 989-998
I would like to thank the members of Lab6@NZ for their support, especially
my supervisor Christian Hartinger for providing countless research advices.
Biological evaluation of selected complexes shows that they are
considerably potent, especially in the HCT116 cell line with low IC50 values.
Currently, the aqueous stability, DMSO stability and acid stability of these
complexes are still being investigated using NMR and ESI-MS methods.
Their redox properties are also looked at using cyclic voltammetry.
Future work involves the complete evaluation of anticancer activity of these
complexes and if possible, establishing the structure-activity relationships
for these two series of compounds.
Ferrocifen is a remarkable
example derived from the breast
cancer drug tamoxifen. The
ferrocene moiety can enhance
the formation of ROS (reactive
oxygen species) which promotes
cell cycle arrest and cellular
senescence.
Compounds Synthesised
The aqueous stability of complex 2a was investigated using 1H-NMR
spectroscopy. 50% DMSO was used to dissolve the compound due to the
poor solubility of the complex. DMSO exchange occurred after 3 hours.
However, the 100mM saline solution can suppress hydrolysis for a
minimum of 3 hours. This implies that while the compound is being
transported in the blood stream,
it can remain stable for a
moderate period of time.
T=48h
T=3h
T=10min
50% DMSO in D2O + 100mM NaCl
Hydrolysis
DMSO species
Protein Targeting
DNA Targeting
Cancer
Cell Cycle Arrest