Nitric oxide (NO) is a potent and multifaceted bioregulatory agent. This project is aimed at a) finding ways to target NO to specific sites in the body for important research and/or therapeutic applications and b) characterizing the possible role of NO as a determinant of cancer risk. Our focus during the past year has been on elucidating the fundamental chemistry of the NO-releasing diazeniumdiolates (compounds containing the [N(O)NO] functional group) with an eye toward using our accumulating knowledge in this area to solve important research and clinical problems. Specifically, we are using the knowledge gained in our basic research investigations into the structure, spectra, dissociation to NO, alkylation, arylation, and photodegradation of the diazeniumdiolate functional group to design prodrugs that are stable at physiological pH but that can be activated to generate NO by enzymatic action. An example developed during the current reporting period is AcOM-PYRRO/NO, an esterase-sensitive diazeniumdiolate that penetrates the cell and generates NO within the cytoplasm on esterase-induced hydrolysis; AcOM-PYRRO/NO proved to be more than two orders of magnitude more potent as an inducer of apoptosis in HL-60 leukemia cells in culture than the spontaneously dissociating parent ion, PYRRO/NO. A second achievement has been the design of agents that can be activated for NO release by enzymes of the glutathione S-transferase (GST) family. The pi isoform of GST is overexpressed in some tumor cells, rendering them resistant to several lines of anticancer therapy, while the alpha isoform is vital to proper cell function. By exploiting the growing knowledge about the structures of the GSTs active sites, we have gone from an initial drug candidate whose alpha:pi rate ratio was 100 to a third generation analogue with a ratio of 0.3. If enough additional selectivity can be designed into this series, a drug capable of irreversibly inhibiting the pi enzyme while sparing the alpha may be forthcoming.We will place particular emphasis during the coming year on designing additional drugs and devices capable of targeting NO release to selected tissues for use as research tools and for possible therapeutic benefit. - Carcinogenesis, Mutagenesis, Nitric oxide, Pharmacology, Toxicology,
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