Investigating The Anti-tumor Mechanism of a Phenanthroline-based Drug
Authors:Jack Eichler, Elma Frias
Mentor:Jack E, Assistant Professor of Pedagogy, University of California Riverside
Previously synthesized phenanthroline-based ligands have been found to possess significantly higher cancer cell cytotoxicity than cisplatin, a leading cancer therapeutic. In an effort to assess the mechanism by which these ligands might cause tumor cell death, iron binding and removal experiments have been considered. Iron is essential for various biological processes including oxygen transport, the synthesis of DNA, and electron transport. The close linkage between cell proliferation and intracellular iron concentrations suggest that iron deprivation strategies may be a mechanism involved in inhibiting tumor cell growth. A series of phenanthroline-based ligands [1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (methylphen), and 2,9-disecbutyl-1,10-phenanthroline(secbutylphen)] was reacted with iron(III) chloride to yield [FeCl4]- complex ions with protonated phen ligands (RphenH+): [phenH][Fe(Cl)4], [methylphenH][Fe(Cl)4] , and [secbutylphenH][Fe(Cl)4]. These model complexes were reacted with excess ethylenediaminetetraacetic acid (EDTA), a known iron chelator, and it was found that the [secbutylphenH][Fe(Cl)4] complex ion was most stable in solution.EDTA binding studies were also conducted in order to quantify the Rphen-Fe binding constant (Kb), and thus provide further evidence that the secbutylphen ligand has a better affinity to bind to iron. Initial experiments demonstrate that increasing concentrations of EDTA do indeed decrease the stability of the Rphen-Fe complex ions, and an analysis aimed at comparing the Rphen-Fe binding constants for the three complex ions is currently underway. Ultimately, the definitive objective is to determine the extent of the correlation between iron binding and cancer cell cytotoxicity for this class of polypyridyl ligands.