This document discusses the potential roles of ruthenium as anticancer compounds in biology, chemistry and medicine. Ruthenium complexes have shown promising anticancer activity both in vitro and in vivo, as they are less toxic and do not induce resistance in cancer cells like platinum-based drugs. Ruthenium can efficiently target cancer cells due to its ability to bind serum proteins like transferrin and its changing oxidation states in cancer versus healthy cells. Several ruthenium complexes are under clinical evaluation and show cell death through DNA binding or targeting cellular signaling pathways involved in cancer.

1. “RUTHENIUM ROLES IN BIOLOGY, CHEMISTRY
AND MEDICINE AS ANTICANCER COMPOUNDS”
FATEMEH BABAEI
CITY UNIVERSITY OF HONG KONG
NOVEMBER 2011

2. What does the
?
word cancer
mean to you?

4. While cancer can affect people of all ages, and a few types of cancer are more
common in children, the risk of developing cancer generally increases with
age. In 2007, cancer caused about 13% of all human deaths worldwide
(7.9 million). Rates are rising as more people live to an old age and as mass
lifestyle changes occur in the developing world.

6. Ruthenium has found its way into the clinic :
 Radiophysical properties of Ru can be applied to radiodiagnostic
imaging
 Immunosuppressants
 Antimicrobials (against malaria and Chaga s disease)
 Antibiotics (against Salmonella typhi and Enterobacteria faecalis
 Nitrosyl delivery/scavenger tools
 Vasodilator/vasoconstrictor agents
 Ruthenium compounds are known to be less toxic and
no cross resistant than platinum counterpart.
 Cancer chemotherapy
Ruthenium has a range of oxidation state (II,III and IV)
accessible under physiological Condition, which is unique
among the platinum-group metals.

7. Cancer cells
Cancer cells need considerably more energy than healthy cells. Their metabolism runs at full
speed and requires large amounts of micronutrients, particularly iron.
Ruthenium
Ruthenium have the ability to bind albumin and transferrin And because cancer cells
need more Iron, transferrin receptors are over expressed, Thereby allowing ruthenium-
based drugs to be more efficiently delivered to cancer cells.

8. The oxidation state changes of ruthenium (II/III) in cancer and healthy cells
“activation by reduction” mechanism

9. Classification of ruthenium complexes with anticancer properties
 Ammine-chlorido derivatives
The cytotoxicity tests had disappointing results
Poor water solubility
 Dimethylsulfoxide complexes
Water soluble
Anti metastatic activity
No cross resistant
 Ruthenium polyaminocarboxylate complexes
Similar to biological molecules,
Low systematic toxicity,
Binding to DNA and alter the normal conformation
and inducing the DNA cleavage
 Organoruthenium complexes

10. Typical structure of ruthenium complexes
Typically, the Organomtallic anticancer complexes
have a half-sandwich “piano-stool” [(g6-arene)
Ru(X)(Y)(Z)] structure.
As shown in the figure, the complexes consist of
three main building blocks, the arene forms the seat
of piano stool and the ligands resemble the legs.
Linking the ligands Y and Z to form a bidentate
chelating ligand (L) seems to be advantageous for
anticancer activity. IC50 values of Ru(II) arene complexes, carboplatin
and cisplatin in A2780 human ovarian cancer cells
after 24 h drug exposure.
Cytotoxic activity
Activity appears to increase with the size of the
coordinated arene: benzene < p-cymene < bi-
phenyle < dihydroantracene <
tetrahydroantracene, in this cell line, the arene =
biphenyle complex has similar cytotoxicity to
the anticancer drug carboplatin.

11. How these drugs work: mechanisms of action
Cancer therapy
Classical way: ruthenium coordinatively
bind to DNA double helix via nitrogen atoms New method : “targeted therapy”
The reactivity of the various binding sites of  Targeting cellular signaling pathway
nucleobases towards Ru (II) at neutral pH  Highly effective and specific
decreases in the order G (N7) > T (N3) >  Side effects are less sever &controllable
C(N3) > A(N7), A(N1). cytotoxicity
The factors that up-regulated in cancer cells are:
The preferable binding is with guanine epidermal growth factor receptor
over adenine, same as cisplatin. (EGFR), vascular endothelial growth factor
(VEGF), cyclin-dependent kinases (CDK).

12. Interactions within guanine (G) and adenine (A) adducts of arene Ru-en
anticancer complexes
when the size of Arene increased, it seems that the hydrophobic arene- purine base
π-π stacking interactions will be increased.

13. Ruthenium complexes with anticancer properties
 NAMI-A binds strongly to serum proteins, including the iron transporter transferrin
and it induces cell arrest in the premitotic G (2)-M phase.
 KP1019 drug induce cell death and have a significant cytotoxicity in vitro against
colorectal cell lines SW480 and HT29. This drug was also found to be highly
effective in in vivo tests and it induces apoptosis in colorectal cell lines mainly via the
intrinsic mitochondria apoptosis pathway.
Clinically evaluated ruthenium-based anticancer drugs

14. Strategy to tether Organometallic ruthenium arene anticancer compounds to recombinant
Human Serum Albumin
 The main role of Human serum
albumin (HSA) is to maintain the osmotic
pressure in the blood and to scavenge free
radicals as an antioxidant.
 HSA is known to accumulate in tumors.
 The carrier conjugate of various
organic anticancer drugs such as
chlorambucil, doxorubicin, and paclitaxel.
RAPTA: 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]-
decane ligand

15. Strategy to tether Organometallic ruthenium arene anticancer compounds to
recombinant Human Serum Albumin
RAPTA-C, theprototype compound with a p-cymene ring
According to these results Organometallic ruthenium (II)-arene anticancer
compound to rHSA could collected in tumor cells, and rHAS could be taken
as a carrier biomolecules for drug delivery of RAPTA complexes in vivo, but
in these area of targeted drug delivery more researches are needed.

16. Reactions with other amino acids and proteins
 Researchers showed (η6-benzene) Ru (DMSO) Cl2 strongly inhibit topoisomerase II activity
by cleavage complex formation. They suggest that the ruthenium complex interacts with DNA
and forms cross links with topoisomerase II. The complex exhibited antiproliferative activity in
vitro.
 Prof. Sadler and his colleagues found that the reaction of [(η6 -Bip) Ru(en)Cl][PF6] complex
with thiol containing amino acids L-cysteine is slow in aqueous solution, and they showed that
thiols couldn’t directly inactive Ru (II)-en arene complexes in blood plasma or in the cells. The
similar results also were found for L-methionine amino acid.
 Sulfur containing ligands in ruthenium compounds also could rapidly react with guanine and
displaced by this nucleobase. Although glutathione intermediates could help for the ruthenation
of DNA or RNA in redox mediated pathway.
 Other studies on cytochrom C and this compound, [(η 6-Bip)Ru(en)Cl][PF6] , have been done
and 2D [1H, 15N] HSQC NMR results showed that the ruthenium complexes are bound to
carboxylate groups (ca. 30%) and the amino terminus (ca. 70%), instead of the histidine
residues, of cytochrome c.
 In summary, in comparison with DNA, amino acids and proteins have lower reactivity to
ruthenium compounds. The result of this point could be less toxicity and side effects of these
compounds. In addition, relatively weak binding of amino acids and proteins to these compounds
could make them great candidate for transport and delivery of these drugs to cancer cells.

17. conclusion
Based on many researches groups’ results, ruthenium arene
complexes showed promising anticancer activity in vitro and in
vivo. These complexes are non-cross-resistant towards cancer
cells and they became good candidates as anticancer agents but
more researches and clinical trials are needed to prove its safety
and low systemic toxicity and its efficacy.

18. Acknowledgements
Prof. Richard H. Fish
My dear classmates
Professors :Sadler, Dyson, Hartinger, Juillerat-Jeanneret, Clarke, and other
research groups
Questions
&
Answers