Diazeniumdiolates, ions of structure R2N[N(O)NO]-, derived from secondary amines, have seen increasing use as nitric oxide (NO)- generating agents for biomedical research applications because of their ability to generate NO spontaneously in physiological fluids. Although their NO donor properties have been extensively studied in buffered aqueous solutions, relatively little is known about their reaction behavior in the more complex milieu encountered biologically. Since they are frequently being targeted at specific biological sites and cell types, a need for such information has become apparent. In the work proposed, the NO release characteristics of anionic and zwitterion diazeniumdiolate substrates will be examined in biomimetic surfactant media that simulate a range of reaction conditions encountered biologically. In particular charged aqueous interfaces of surfactant micelles, oil-in-water and water-in-oil microemulsions, and natural lipid surfactant liposomes will be used to assess the effect of complex hydrophilic/hydrophobic environments, such as biological membranes and protein surfaces, on diazeniumdiolate dissociation rates. Data obtained in the different microenvironments provided by the surfactant aggregates will also be used to obtain a better understanding of electronic polarization effects and structure-reactivity relationships that control the release NO from this important class of nitric oxide donor compound. It is also proposed to study the effect of pH gradients across liposome lipid bilayers on NO release rates of donor compounds contained within liposome interiors. Data obtained from this phase of the project will have potential applications in the physical targeting of diazeniumdiolates at biological sites, of infection or tumors, that typically have a lower pH than healthy tissue. Liposome transport of diazeniumdiolates would have the advantage of avoiding the systemic distribution of the donor compounds and exposure of sensitive parts of the body to the multipotent effects of NO.
| Dinh, Bach; Dove, Kevin; Jappar, Dilara et al. (2005) Effect of hydrophobic structure on the catalysis of nitric oxide release from zwitterionic diazeniumdiolates in surfactant and liposome media. Nitric Oxide 13:204-9 |
