Design of Metallocene Complexes with Antitumor Properties

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The proposed research is aimed at the understanding of the structure-activity relationship of metallic antitumor agents. Chemotherapy is one of the alternatives to treat this life-threatening disease and metal complexes have an important role in the area. Thus, the long term objective is, using the structure-activity relationship, to design novel metal complexes with the desired antitumor activity and to understand the mechanism of action at molecular levels. The study is focused on the synthesis, chemical and biochemical characterization and biological activity profile of functionalized Cyclopentadienyl metallocenes (M = Ti(IV), V(IV) and Mo(IV)) derivatives containing amino acids and hydrophilic groups as ancillary ligands. The parent compound, Cp2TiCI2 is active against colorectal, lung and breast carcinomas therefore, the new derivatives may have similar antitumor activity profile. However, their activity will be determined by mean of the biological activity study. The specific objectives of this project are: 1) Synthesis and characterization of new R-Cp2MX2 (M = Ti(IV), V(IV) and Mo(IV), R = carboalkoxy) complexes containing amino acids and hydrophilic groups as ancillary ligands. Due to the hydrolytic stability imparted by functionalized Cp ring and water solubility imparted by the hydrophilic ligands, these complexes are expected to be compatible to physiological conditions while retaining the labile character as function of pH, being able to release the metal ion in solution. 2) Ligand hydrolysis (Cp and L). This will be monitored by UV-VIS and 1H NMR spectroscopies. This objective provides vital information regarding to the stability and decomposition pattern of these complexes in aqueous solution. 3) Metal-Biomolecule (DNA, oligonucleotide, glutathione) interaction studies will be pursued in order to gain insights with regard to the mechanism of action, binding constants and binding specificity/selectivity and possible mechanism of transport and/or deactivation. 4) Biological screening of new Ti(IV), V(IV) and Mo(IV) complexes will be performed at the Biotesting Lab, UPR-Mayaguez. The screening efforts are intended to find Ti(IV), V(IV) and Mo(IV) complexes with potential therapeutic uses. This research will afford valuable information to the understanding of the structure-activity relationship of antitumor metallic species. Also it lays grounds for the rational design of new organometallic antineoplastic agents.