In the broadest sense, the long term objective of this research project is to develop novel structural analogs of the anticancer compound cis- Pt(NH3)2Cl2, cisplatin, as well as to contribute to the understanding of the mechanism of action of platinum antitumor drugs. Within its context, the specific aims of this research are: (1) To determine whether the selective substitution of the ammine (-NH3) ligands of the cisplatin complex by a series of other ligands, including imidazole, thiazole and oxazole derivatives will result in increased antitumor activity or decreased toxicity; (2) To obtain structural information on the interaction of the new platinum complexes with DNA; and (3) To obtain information about the mechanism of action of """"""""second generation"""""""" platinum antitumor complexes of the type cis-[Pt(NH3)2(A)Cl]+, where A stands for a planar nitrogen-donor ligand. In order to accomplish these goals, a series of new platinum complexes will be prepared. The synthetic approach will be focused in complexes with formulas cis-[Pt(NH3)2(A)Cl]+ and cis-[Pt(NH3)(A)Cl2, where A stands for an azole derivative. The cationic complexes are expected to possess a different mechanism for interaction with DNA as is seemingly the case for the analogous pyridine complexes that have been reported in the literature. The interaction of the new complexes with plasmid DNA, calf thymus DNA, and polynucleotides will be examined using biophysical and biochemical techniques. Raman spectroscopy will be used to asses their binding sites, and to characterize the perturbations to DNA secondary ad tertiary structure induced by these new complexes. Restriction enzymes will be used to probe the specific binding of the platinum complexes; and gel electrophoretic mobility shift assays will be used to determine the unwinding angles that are induced by the coordination of the platinum to plasmid DNA. The new compounds will be tested in a panel of cancer cell lines to examine their cytotoxic activity. Emphasis will be given to test the new compounds in breast and colon cancer cell lines, systems that show intrinsic resistance to cisplatin and to other chemotherapeutic agents. Some of the reported cationic antitumor complexes will be prepared, and their binding to DNA will be studied by Raman spectroscopy. The development of new platinum antitumor drugs is needed to improve the chemotherapeutic approach to cancer treatment.

Project Start
1997-05-01
Project End
1998-04-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
24
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Puerto Rico Mayaguez
Department
Type
DUNS #
City
Mayaguez
State
PR
Country
United States
Zip Code
00681
Díaz Casas, Adalberto; Chazin, Walter J; Pastrana-Ríos, Belinda (2017) Prp40 Homolog A Is a Novel Centrin Target. Biophys J 112:2529-2539
Lara Rodriguez, L; Sundaram, P A (2016) Corrosion behavior of plasma electrolytically oxidized gamma titanium aluminide alloy in simulated body fluid. Mater Chem Phys 181:67-77
Bueno-Vera, J A; Torres-Zapata, I; Sundaram, P A et al. (2015) Electrochemical characterization of MC3T3-E1 cells cultured on ?TiAl and Ti-6Al-4V alloys. Bioelectrochemistry 106:316-27
Pastrana-Rios, Belinda; Del Valle Sosa, Liliana; Santiago, Jorge (2015) Trifluoroacetic acid as excipient destabilizes melittin causing the selective aggregation of melittin within the centrin-melittin-trifluoroacetic acid complex. Struct Dyn 2:041711
Santiago-Medina, P; Sundaram, P A; Diffoot-Carlo, N (2015) Titanium Oxide: A Bioactive Factor in Osteoblast Differentiation. Int J Dent 2015:357653
Santiago-Medina, Pricilla; Sundaram, Paul A; Diffoot-Carlo, Nanette (2014) The effects of micro arc oxidation of gamma titanium aluminide surfaces on osteoblast adhesion and differentiation. J Mater Sci Mater Med 25:1577-87
Vera, José L; Rullán, Jorge; Santos, Natasha et al. (2014) Functionalized ferrocenes: The role of the para substituent on the phenoxy pendant group. J Organomet Chem 749:204-214
Lara Rodriguez, L; Sundaram, P A; Rosim-Fachini, E et al. (2014) Plasma electrolytic oxidation coatings on ?TiAl alloy for potential biomedical applications. J Biomed Mater Res B Appl Biomater 102:988-1001
Dominguez-Garcia, Moralba; Ortega-Zuniga, Carlos; Melendez, Enrique (2013) New tungstenocenes containing 3-hydroxy-4-pyrone ligands: antiproliferative activity on HT-29 and MCF-7 cell lines and binding to human serum albumin studied by fluorescence spectroscopy and molecular modeling methods. J Biol Inorg Chem 18:195-209
Pastrana-Rios, Belinda; Reyes, Myrna; De Orbeta, Jessica et al. (2013) Relative stability of human centrins and its relationship to calcium binding. Biochemistry 52:1236-48

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