Design and synthesis of nucleic acid templated and targeted drugs and probes

Traditional chemotherapeutic approaches to cure viral infections and cancer greatly depend on drugs that are selectively toxic to the disease-causing organism or diseased cells. Most currently used anticancer drugs do not show good selectivity because of the similarity between the diseased cells and normal cells, while most antiviral drugs, though highly specific, do not destroy-the virus itself. Advances in genomic sequencing and DNA chip technology have spurred an interest in Waston-Crick antisense and antigene approaches to chemotherapy. As promising as these approaches are, it is hard to predict the therapeutic effect of targeting a viral or cancer-specific nucleic acid sequence, and it's not clear that antigene agents are specific enough to restrict their action to the target sequence only. A number of years ago, our group proposed a new concept for patient-specific chemotherapy, which also makes direct use of genetic information about the disease cells. The key idea is to use the mRNA specific to a disease state, not as a target, but as a template to promote the association of a prodrug and a catalytic component capable of releasing the cytotoxic drug, which then kills the diseased cell. Such a system could also be used for diagnosis of diseases, by triggering the activation of reporter molecules, such as a fluorophore.;In this dissertation, we describe further improvements to peptide nucleic acid-based prodrug and probe activation system that we have previously developed. We describe the design and synthesis of a new modified PNA building block that can be used to directly tether the catalytic and prodrug or probe components to the base portion of a PNA. In doing so, we showed that the prodrug and probe activation efficiency can be improved about seven times, depending on its attachment point, compared to the previous system in which the catalyst and prodrug were tethered to the ends of the PNAs.;We also developed a new method for mRNA-triggered fluorescent probe activation using the Staudinger reaction. In this system, a fluorescein derivative linked to a PNA was rendered non-fluorescent by forming an ester linkage to ortho-carboxy triphenylphosphine. When incubated with a PNA bearing an alpha-azidoacetamide group in the presence of a DNA template complementary to both PNAs, a fluorescent signal was produced.;Another one of our research goals was to develop an efficient and specific anti-gene agent which could enhance heat induced radiosensitization (HIR) of killing tumors by blocking heat shock protein 70 (HSP70) production. Recently it has been shown that knockouts of HSP70, which is produced in response to heat, make cells more susceptible to killing by a combination of heat and radiation. We describe the design, synthesis and characterization of polyamides designed to bind to the heat shock element of HSP70, and thereby block transcription of HSP70 by blocking binding of the heat shock transcription factor.