While cancer can affect people of all ages, and a few types of cancer are morecommon in children, the risk of developing cancer generally increases withage. 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 masslifestyle 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 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.
Cancer cellsCancer 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.
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 complexesTypically, the Organomtallic anticancer complexeshave a half-sandwich “piano-stool” [(g6-arene)Ru(X)(Y)(Z)] structure.As shown in the figure, the complexes consist ofthree main building blocks, the arene forms the seatof piano stool and the ligands resemble the legs.Linking the ligands Y and Z to form a bidentatechelating ligand (L) seems to be advantageous foranticancer activity. IC50 values of Ru(II) arene complexes, carboplatin and cisplatin in A2780 human ovarian cancer cells after 24 h drug exposure. Cytotoxic activityActivity appears to increase with the size of thecoordinated arene: benzene < p-cymene < bi-phenyle < dihydroantracene <tetrahydroantracene, in this cell line, the arene =biphenyle complex has similar cytotoxicity tothe anticancer drug carboplatin.
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 pathwaynucleobases towards Ru (II) at neutral pH Highly effective and specificdecreases in the order G (N7) > T (N3) > Side effects are less sever &controllableC(N3) > A(N7), A(N1). cytotoxicity The factors that up-regulated in cancer cells are:The preferable binding is with guanine epidermal growth factor receptorover adenine, same as cisplatin. (EGFR), vascular endothelial growth factor (VEGF), cyclin-dependent kinases (CDK).
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.
Ruthenium complexes with anticancer properties NAMI-A binds strongly to serum proteins, including the iron transporter transferrinand it induces cell arrest in the premitotic G (2)-M phase. KP1019 drug induce cell death and have a significant cytotoxicity in vitro againstcolorectal cell lines SW480 and HT29. This drug was also found to be highlyeffective in in vivo tests and it induces apoptosis in colorectal cell lines mainly via theintrinsic mitochondria apoptosis pathway. Clinically evaluated ruthenium-based anticancer drugs
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[220.127.116.11]- decane ligand
Strategy to tether Organometallic ruthenium arene anticancer compounds to recombinant Human Serum Albumin RAPTA-C, theprototype compound with a p-cymene ringAccording to these results Organometallic ruthenium (II)-arene anticancercompound 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 activityby cleavage complex formation. They suggest that the ruthenium complex interacts with DNAand forms cross links with topoisomerase II. The complex exhibited antiproliferative activity invitro. Prof. Sadler and his colleagues found that the reaction of [(η6 -Bip) Ru(en)Cl][PF6] complexwith thiol containing amino acids L-cysteine is slow in aqueous solution, and they showed thatthiols couldn’t directly inactive Ru (II)-en arene complexes in blood plasma or in the cells. Thesimilar results also were found for L-methionine amino acid. Sulfur containing ligands in ruthenium compounds also could rapidly react with guanine anddisplaced by this nucleobase. Although glutathione intermediates could help for the ruthenationof DNA or RNA in redox mediated pathway. Other studies on cytochrom C and this compound, [(η 6-Bip)Ru(en)Cl][PF6] , have been doneand 2D [1H, 15N] HSQC NMR results showed that the ruthenium complexes are bound tocarboxylate groups (ca. 30%) and the amino terminus (ca. 70%), instead of the histidineresidues, of cytochrome c. In summary, in comparison with DNA, amino acids and proteins have lower reactivity toruthenium compounds. The result of this point could be less toxicity and side effects of thesecompounds. In addition, relatively weak binding of amino acids and proteins to these compoundscould make them great candidate for transport and delivery of these drugs to cancer cells.
conclusionBased on many researches groups’ results, ruthenium arenecomplexes showed promising anticancer activity in vitro and invivo. These complexes are non-cross-resistant towards cancercells and they became good candidates as anticancer agents butmore researches and clinical trials are needed to prove its safetyand low systemic toxicity and its efficacy.
AcknowledgementsProf. Richard H. FishMy dear classmatesProfessors :Sadler, Dyson, Hartinger, Juillerat-Jeanneret, Clarke, and otherresearch groups Questions & Answers