Post on 31-May-2015
transcript
“RUTHENIUM ROLES IN BIOLOGY, CHEMISTRY AND MEDICINE AS
ANTICANCER COMPOUNDS”
FATEMEH BABAEICITY UNIVERSITY OF HONG KONG
NOVEMBER 2011
What does the word
cancer mean to you?
?
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.
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
Cancer chemotherapy
Ruthenium compounds are known to be less toxic and no cross resistant than platinum counterpart.
Ruthenium has a range of oxidation state (II,III and IV)accessible under physiological Condition, which is unique among the platinum-group metals.
Cancer cells need considerably more energy than healthy cells. Their metabolism runs at full speed and requires large amounts of micronutrients, particularly iron.
Cancer cells
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.
The oxidation state changes of ruthenium (II/III) in cancer and healthy cells
“activation by reduction” mechanism
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
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.
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.
IC50 values of Ru(II) arene complexes, carboplatin and cisplatin in A2780 human ovarian cancer cells after 24 h drug exposure.
Cytotoxic activity
How these drugs work: mechanisms of action
Cancer therapy
Targeting cellular signaling pathway Highly effective and specific Side effects are less sever &controllable cytotoxicity
New method : “targeted therapy”
The factors that up-regulated in cancer cells are: epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclin-dependent kinases (CDK).
Classical way: ruthenium coordinatively bind to DNA double helix via nitrogen atoms
The reactivity of the various binding sites of nucleobases towards Ru (II) at neutral pH decreases in the order G (N7) > T (N3) > C(N3) > A(N7), A(N1).
The preferable binding is with guanine over adenine, same as cisplatin.
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.
Clinically evaluated ruthenium-based anticancer drugs
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.
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
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.
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.
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.
Questions &
Answers
Acknowledgements
Prof. Richard H. Fish
My dear classmates Professors :Sadler, Dyson, Hartinger, Juillerat-Jeanneret, Clarke, and other research groups