Synthesis and DNA interactions of sterically-friendly copper(II) porphyrins
Abstract
Approximately 80-85% of proliferating tumor cells contain the enzyme telomerase, which prolongs cell life by elongating the telomeres. Research has shown that folding of telomeric DNA into a four-stranded structure known as a quadruplex can block the activity of telomerase, which eventually leads to cell death. Quadruplexes are stabilized with sodium and potassium cations but may also be stabilized with aromatic ligands, like porphyrins. Copper(II) porphyrins are especially useful ligands due to their unique emission properties--in coordinating solvents emission is quenched, but is seen when protected by binding to DNA. The subsequent chapters describe the synthesis and DNA interactions of copper(II) porphyrins with single-stranded DNA, unimolecular and bimolecular quadruplex DNA. Methods employed include absorbance, emission and circular dichroism (CD) spectroscopies. Chapter one details the synthesis and characterization of the sterically-friendly copper(II) porphyrin (5,15-di(N-methylpyridinium-4-yl)porphyrinato)copper(II), Cu(tD4). Chapter two begins the DNA studies of the sterically-friendly porphyrin and the literature standard (5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrinato)copper(II), Cu(T4), through studies of single-stranded DNA hosts. The single-stranded DNA hosts were used as a type of reference point for the quadruplex studies and gave insights into the two-base pocket DNA internalization of porphyrin ligands called interdigitation. It was found that the sterically-friendly porphyrin was able to interdigitate into all of the single-stranded DNA hosts, whereas the interactions of the bulky porphyrin where limited due to its steric constraints. Chapter three gives the results of the studies of the two copper(II) porphyrins with quadruplex DNA. Bimolecular and unimolecular quadruplex sequences were studied, which represented a variety of structural features found in quadruplexes. It was found that the sterically-friendly porphyrin was better internalized into quadruplex DNA than the bulky porphyrin. Overall, it was found that the emission studies used here better define the interactions of copper(II) porphyrins with DNA than circular dichroism(CD), which is often the spectroscopy of choice in the literature for ligand-DNA studies. The CD signals induced from the interactions of porphyrins with DNA, or ICD signals, were shown to be highly dependent on the environment in which the porphyrin-DNA interaction took place.
Degree
Ph.D.
Advisors
McMillin, Purdue University.
Subject Area
Biochemistry|Inorganic chemistry
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