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Design of Ti(IV) and Mo(IV) Complexes with Antitumor Properties: Synthesis and biochemical Characterization

Abstract

The proposed research is aimed at the understanding of the structure-activity relationship of metallic antitumor agents. The long term objective is, using the structure-activity relationship, to design novel metal complexes with the desired antitumor activity.

The study is focused on the synthesis, chemical and biochemical characterization and biological activity profile of Ti(IV) and Mo(IV) derivatives containing amino acids and amino acid based ligands. The parent compound, Cp2TiCl2 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:

  • Synthesis and characterization of new Ti(IV) and Mo(IV) complexes containing amino acids and amino acid based ligands. This will be accomplished by replacing Cl- (for Cp2MoCl2) and Cl- and Cp for Ti(IV) and Mo(IV) complexes for L-cysteine, L-methionine, D-penicillamine, L-alanine and LL-CH6. Due to the water solubility imparted by these ligands, these complexes are expected to be compatible to physiological conditions and to possess labile character as function of pH, being able to release the metal ion in solution.
  • Ligand hydrolysis (Cp and L) and Metal release studies. 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.
  • DNA-Metal and Oligonucleotide-Metal interaction studies will be pursued in order to gain insights with regard to the mechanism of action, binding constants and related thermodynamic parameters and binding specificity and selectivity.
  • Electrochemical studies. The electrochemical studies of Ti(IV) and Mo(IV) complexes will be carried out in organic and aqueous (buffer) solutions to characterize their redox behavior. Cyclic voltammetry of the complexes in presence of calf-thymus DNA will be performed to observe the redox behavior changes (potentials and currents) and extrapolate mechanistic information and rate constants for oxidation of DNA.
  • Biological screening of new Ti(IV) and Mo(IV) complexes will be performed at the Biotesting Lab, UPR-Rio Piedras. The screening efforts are intended to find Ti(IV) and Mo(IV) complexes with potential therapeutic uses. This research will afford valuable information to the understanding of the str ucture-activity relationship of antitumor metallic species. Also it lays grounds for the rational design of new organometallic and inorganic antineoplastic agents.

Publications

Tulio E. Chávez-Gil , Enrique Meléndez .
"Synthesis, spectroscopic and electrochemical characterization of water soluble
[( small eta, Greek5-C5H5)2Mo(thionucleobase/thionucleoside)]Cl2 complexes"
.
Inorganica Chimica Acta . Volume 357, Issue 4, March 2004, Pages 1092-1102 .

Vilmarí López-Ramos , Carmen A. Vega, Mayra Cádiz and Enrique Meléndez.
"Electrochemical and spectroscopic analysis of the interaction of molybdenocene dichloride with nitrogen bases". Journal of Electroanalytical Chemistry .Volume 565, Issue 1 , April 2004, Pages 77-83.

Lopez-Ramos, V., Vega , C.A. , Cadiz , M., Melendez, E. “ Electrochemical and spectroscopic analysis of interactions of molydenocene dichloride with nitrogen bases”. Journal of Electroanalytical Chemistry 565, pp. 77-93, 2004

Yajaira Pérez, Vilmari López, Luis Rivera-Rivera, Aracelis Cardona and Enrique Meléndez.
"Water-soluble titanocene complexes with sulfur-containing aminoacids: synthesis, spectroscopic, electrochemical and Ti(IV)–transferrin interaction studies". Journal of Biological Inorganic Chemistry. Volume 10, Number 2. March 2005. Pages: 94 - 104.

María I. Rodríguez, Tulio Chávez-Gil, Yasiris Colón, Naomi Díaz and Enrique Meléndez.
"Molybdenocene–DNA interaction studies using electrochemical analysis". Journal of Electroanalytical Chemistry, Volume 576, Issue 2, March 2005, Pages 315-322.

Tulio E. Chávez-Gil , Enrique Meléndez .
"Synthesis, spectroscopic and electrochemical characterization of water soluble [( 5-C5H5)2Mo(thionucleobase/thionucleoside)]Cl2 complexes". Inorganica Chimica Acta . Volume 357, Issue 4, March 2004, Pages 1092-1102 .

José L. Vera, Félix R. Román and Enrique Meléndez.
"Study of titanocene–DNA and molybdenocene–DNA interactions by inductively coupled plasma–atomic emission spectroscopy". Analytical and Bioanalytical Chemistry. Volume 379, Number 3. June 2004. Pages: 399 - 403.




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