Cisplatin. Katharina Jeschonek, Alina Hanlon, Alexander Nolzen, Stefan Knoche. Studienprojekt DaMocles Wintersemester 2011/2012

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1 Cisplatin Katharina Jeschonek, Alina Hanlon, Alexander Nolzen, Stefan Knoche Studienprojekt DaMocles Wintersemester 2011/2012 History Cis-diamminedichloroplatinum was first synthesized by Michael Peyrone ( ), an italian chemist, in He called the substance Peyrone's salt or also known as Peyrone's chloride. In 1893, Alfred Werner explored the exact structure of the molecule and discovered, that two amines and two chlorides are coordinating with a platinum atom. But only 60 years after, the chemotherapeutic effect of cis-diamminedichloroplatinum was found by accident. In 1964 Barnett Rosenberg, a professor for biophysics and chemistry at the Michigan State University, researched the Escherichia Coli (E Coli) with the aid of alternating current. For this he used platinum electrodes and figured out, that the E coli cells still grow, but the cell division had stopped. The reason for that was not the alternating current as supposed, but least amount of planimum chipped of the electrodes. After some other experiments Rosenberg was sure, platinum complexes can even stop tumor cells. Cisplatin was found as most efficient substance. The name Cisplatin the substance obtained in 1978 when the substance was permitted in chemotherapeutic use. Synthesis Synthesis scheme:

2 Mechanism: All ligand exchanges take place on a platinum-associatively activated mechanism (SN2), thus forming a five-coordinate bipyramidal, noble gas-configured transition state. Procedure: The precursor, K2[PtCl4], is merged with a saturated solution of Kl and the result is K2[PtI4] and KCl. For the chemical reaction to be completed, a disproportionately high amount of KI, as a weaker nucleophile (pkb(i-)= 25; pkb(cl-)= 21), is merged. To this is added two NH3 equivalent and the mixture becomes cis- [PtI2(NH3)2] because of the trans-effect*. The reaction takes place quantitatively because ammonia is a much stronger nucleophile (pkb (NH3) = 4.8) then iodide. Cis- [PtI2(NH3)2] is a yellow solid state substance which is filtered, dried and mixed with an aqueous silver nitrate solution. This forms the soluble cis-[pt(oh2)2(nh3)2]2+ and insoluble silver iodide (AgI solubility = 1.59 * * mol2 L-2), which precipitates and therefore also causes this reaction to proceed quantitatively because silver iodide is continuously removed from the thermodynamic equilibrium constant. The silver iodide is filtered off and the solution is mixed with potassium chloride, which leads to the product cisplatin, as a yellow powder which precipitates and can be filtered off. * Trans-effect: The trans-effect was discovered in 1926 by Ilya Tschernjajew and marks the effect of a ligand on the substitution rate of a trans-disposed ligand in the complex chemistry. Therefor it is a kinetic effect. Sorted by the trans-effect (increase of the substitution rate), the result is the following series of trans-directing ligands: F-, H2O, OH- <NH3 <py <Cl-<Br-<I-, SCN-, NO2-, SC (NH2) 2, Ph-<SO32-<PR3 AsR3, SR2,CH 3- <H-, NO, CO, CN-, C2H4. One recognizes that I- has a greater transdirecting effect then Cl-. For this reason, the cisplatin synthesis K2[PtCl4] is first mixed with potassium iodide. Because of the stronger trans-effect of iodine the purity of the produced cisplatin increases. Kurnakow method: The Kurnakow method provides a way to check your samples of their cis-and transplatinum content and is used to quantify the trans platinum impurities in clinical cisplatin. With thiourea added to a sample of Cisplatin the result is a deep yellow solution of [PtTh4]Cl2. Added to Transplatin, it reacts to the white insoluble [Pt(NH3)2Th2]Cl2. The method is based on the stronger trans effect of thiourea compared to chloride.

3 Effect Cisplatin belongs to the group of alkylating agents, who alkylate nucleic acids phasespecific. It is a widely used cytostatic a medium, that cell growth or cell division inhibits. Before Cisplatin can react, it must be activatet only once. In aqueous media, as well as the body fluids, hydrolysis takes place. There are the chloride ligands replaced by water ligands and it will be doubly charged Cisplatin-water-complexes formed. This electrophilic complexes, so-called bio-activated Cisplatin, are now in a position to form adducts with nucleophilic groups of DNA, proteins and small molecules. Cisplatin inhibits the replication of the DNA by various cross-affiliations. Besides linking of proteins and DNA to Cisplatin, there are intrastrand cross-links, where either neighboring bases (1,2-intrastrand cross-link) or bases on another base pair across a strand (1,3-intrastrand cross-link) are linked by Cisplatin. For 1,2-interstrand cross-links are both DNA strands interconnected across adjacent base pairs. These disturb the structure of DNA and thus make it inoperable. Due to this fact it comes to a halt in cellular metabolism, so that the cell initiates apoptosis, the programmed cell death. In particular, the intrastrand cross-links, which make up about 90% of the DNAplatinum adducts, contributing to a massive structural change in the DNA double helix. Therby is the DNA repair inhibited, because repair proteins can bind to DNA worse. For some people, there is a development of resistance to Cisplatin. The reason researchers have published in There exists a DNA polymerase, the polymerase "Eta", which is in a position to over read cross-links and to double the DNA anyway prerequisite for cell division. Thus occurs the cell growth regardless of DNA-platinum adducts, which makes the Cisplatin ineffective. Cisplatin may also cause point mutations. A point mutation is for example an exchange of a base of DNA against another. This results in a coded region to an incorporation of a different amino acid and thus to the transcription of an altered mrna, which in turn leads to an altered protein. This protein can then be no longer fulfill his duties in full. In rare cases, it is also an improvement of the polypeptide. Application Cisplatin is used for its effect in cancer therapy. It is administered intravenously and is found almost exclusively in combination with other chemotherapeutic agents used. Applications are testicular, ovarian, lung, bladder and cervical cancers, as well as tumors in the head and neck region. However, Cisplatin do not work only on fastgrowing tumor cells, but to some extent on healthy body cells.

4 Significance Cisplatin has an essential role in the testicular cancer therapy. Prior to Cisplatinbased therapy, the diagnosis of testicular cancer was practically a death sentence. Meanwhile, by this therapy, the chances of recovery are themselves in metastatic tumors in about 80%. If the forecasts of the healing are already very well, there are even up to 90%, which can be cured. Carboplatin Carboplatin is a chemical substance which is used to medicate different forms of cancer especially lung, head and neck cancers. The substance Carboplation is optimized and more effective related to it s parent compound Cisplatin which had more side-effects. Oxaliplatin Oxaliplatin is a substance used against collorectal cancer. It is a combination of fluoronracil and leucovorin. The effect of a medical treatment with this substance is a blocking function in cell growth furthermore offers a higher survival rate of patients. Satraplatin Satraplatin is a platinum compound used to medicate prostate cancer. If Cisplatin does not react Satraplatin is used as a following therapy. The substance is a platinum(v) complex, through bonding with the DNA it s getting reduced to a platinum(ii) complex. The side-effects of this type of medical treatment are very strong( e.g. vomitus, tinnitus etc.)

5 Sources: Taschenbuch der Chemie von Karl-Heinz Lautenschläger, Werner Schröter und Andrea Wanninger Hollemann & Wiberg, Lehrbuch anorganische Chemie, Auflage 102, Walter de Gruyter & Co., Berlin (pages: , ) * * jpg