Synthesis, characterization and studies of antitumoral activities of Pd(II) and Pt(II) complexes: the interaction of the complexes with DNA, metabolism and cellular uptake

• Grant number: 06/05192-1
• Support Opportunities: Scholarships abroad - Research
• Start date: March 12, 2007
• End date: August 09, 2007
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Mauricio Cavicchioli
• Grantee: Mauricio Cavicchioli
• Host Investigator: Nicholas Patrick Farrell
• Host Institution: Pessoa Física
• Institution abroad: Virginia Commonwealth University (VCU), United States

Abstract

Metal complexes has been used in Medicine for treatment of several diseases and the most widely studied compounds are those used for cancer treatment, specially platinum(II) and palladium(II) complexes. In general, antitumoral and cytotoxic activities of this class of antineoplasic agents are resultant from their interaction with DNA of the cells. DNA is accepted to be the cellular target of cisplatin, cis-[PtCl2(NH3)2], which is the most widely used complex in Medicine and shows significant results of antitumoral activity in the human body. However, these compounds present disadvantages as side effects and resistance of the tumor to the drugs. In order to increase the efficacy and decrease the resistance of the tumor, new platinum compounds have been obtained. These new compounds, as carboplatin and oxaliplatin, belong to a second generation of drugs for chemotherapy. Some strategies that have been used to develop new chemotherapic drugs are the use of new ligands coordinated to platinum and the synthesis of structurally novel complexes. Structurally different complexes should be able to form a distinct pattern of DNA-binding which can make difficult the cellular repair machinery (this machinery provides the resistance of the tumor to the drug). Dinuclear and trinuclear complexes have been synthesized in order to form a distinct pattern of DNA-binding, as for instance, the homotrinuclear BBR3464 or [trans-PtCl(NH3)2)2(u-trans-Pt-(NH3)2(NH2(CH2)6NH2)2)](NO3)4, which was synthesized by the research group of Prof. Nicholas Farrell, of the Commonwealth Virginia University (USA). The complex shows efficacy during the in vivo tests for treatment of tumors which do not respond to cisplatin. At present, this trinuclear complex is under Phase II clinical trials. During this interdisciplinary project, we intend to synthesize new dinuclear and trinuclear palladium(II) and platinum(II) complexes, by using techniques from Prof. Nicholas Farrell’s research laboratory. These complexes will be characterized by spectroscopic techniques. Furthermore, experiments will be evaluated to determine the DNA-binding types, to determine the metabolism how quickly do new drugs react with sulfur-containing biomolecules (Human Serum Albumin, cysteine, glutathione etc.) and to monitor the metal uptake into cells. Antiproliferative tests will also be evaluated using different tumor cell lines from those already tested in Brazil. Biological studies, which are the most important part of the project, will be emphasized, and they will be developed with the complexes prepared in Brazil during our pos-doctoral period. The synthesis and characterization of the compounds have already been done in our laboratories during pos-doctoral studies. However, new techniques of synthesis will be applied during the development of the project in the USA. Until now, biological studies were limited to in vitro tests in order to compare the antiproliferative activities of the complexes with the activities of the chemotherapic drugs available. In the USA, it will be possible to evaluate more deepened studies, which include in vivo antiproliferative and cytotoxic tests against tumor cell lines. Studies regarding DNA interactions and cellular uptake of the drug will also be evaluated. The results obtained will contribute to elucidate the mechanism of action of the compounds. Consequently, the results obtained would be useful to design new complexes which are able to bind to DNA more effectively, in order to increase their antineoplasic activity. (AU)