Nitric oxide (NO) is an important bioregulator that is involved in the control of neurotransmission, blood clotting, and blood pressure. In addition, NO has been shown to kill cancerous tumor cells. Thus, previous research has focused on developing drugs that can deliver NO efficiently and selectively, e.g., to tumor cells without dramatically affecting other bioregulatory processes. Diazeniumdiolates are an interesting class of such drugs presently under development. Recent efforts to make diazeniumdiolates more effective pharmaceuticals have concentrated on using derivatives of such compounds to deliver NO specifically to a targeted site. A major goal of the proposed research is to develop photochemical precursors to diazeniumdiolates that can be used as effective NO-releasing agents. Since initial experiments in other laboratories with classic photoprotecting groups gave unexpected and disappointing results, reaction pathways will be clarified so that more efficient phototriggered NO-releasing drugs can be rationally designed. In addition, if diazeniumdiolates are to enjoy routine medical use, their basic photochemistry must be understood so that phototoxicity issues may be anticipated and avoided The specific aims of the proposed research, which address the above goals, are briefly outlined: (1) Reaction pathways involved in the photochemistry of O-alkylated diazeniumdiolates will be elucidated with product analysis and the powerful tool of time-resolved infrared (TRIR) spectroscopy. (2) Oxygen-substituted nitrenes (O-nitrenes), proposed to be intermediates efficiently produced by photolysis of O-alkylated diazeniumdiolates will be characterized. (3) Since O-nitrenes are a heretofore unstudied class of intermediates their reactivity will be examined in detail by both experimental and computational methods. (4) Ultimately, new O-alkylated diazeniumdiolate derivatives for the efficient photochemical production of NO will be designed and tested.
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