| dc.description.abstract | The thesis titled “Nitrite Releasing Molecules: Synthesis, Mechanism and Potential Application as Prodrugs for the Improvement of Nitric Oxide Bioavailability“ aimed at the development of strategies for the improvement of nitric oxide (NO) bioavailability in mammalian cells. The long term goal of the project was to develop potential drug molecules and strategies to combat cardiovascular diseases such as heart attack, hypertension, stroke, ischemia reperfusion injury, pulmonary thromoembolism, platelet aggregation etc. A decrease in the levels of NO has been found to be a cause of initiation and progression of these diseases. NO is generally produced in human body by a heme-containing enzyme nitric oxide synthase (NOS). When the activity of the natural enzyme NOS is compromised, human body uses an alternate mechanism to improve the bioavailability of NO through reduction of nitrite (NO2─) present in the blood plasma. The reduction of nitrite to NO is mainly carried out by heme proteins (hemoglobin, myoglobin, neuroglobin etc.) in their ferrous Fe(II) form. Under disease conditions, a suitable NO-based therapy is required as both NO and NO2─ levels are affected. As NO2─ is being considered a natural prodrug of NO, synthetic nitrite donors are emerging as potential therapeutic candidates. Therefore, NO and nitrite are the main components of this dissertation. Synthetic NO2─ donors as NO prodrugs have been explored. This thesis contains four chapters.
In Chapter 2, discussion will start with the sequence of events leading to the discovery of 4-nitronaphthalimides (4-NNs) as NO2─ donor NO prodrugs. It was found that 4-NNs were good at releasing NO2─ with assistance of multiple thiols (GSH in mammalian cells) and consequent NO release was found to be mediated by iron(II) proteins, e.g., deoxy-myoglobin Fe(II). It was observed that the reaction of 4-NNs was very specific to thiols and sensitive to various factors such as reaction medium, pH and nature of thiols (nucleophilicity). The compounds showed controlled NO2─ release over a period of 12 hours.
In Chapter 3, the chemical reactivity of nitrite donors will be discussed under different reaction conditions (micellar and non-micellar), different surfactants, thiols with different pKa values and different pH conditions. It was found that cationic surfactants increased thiolate formation, whereas anionic and neutral ones could not. Additionaly, DOSY NMR, DLS & Zeta potential measurements and confocal microscopic studies indicated that 4-NNs localized in palisade layer of micelles, suitable for nucleophilic attack by thiols. Synthesis of 4-NNs with surfcatant-like structures showed enhanced NO2─ release as well as cellular uptake.
In Chapter 4, the development of bifunctional NO donor molecules will be discussed. The bifunctional molecule having ebselen moiety can release nitrite and eliminate harmful peroxynitrite simultaneously. This compound was found to release nitrite as well as scavenge peroxynitrite with low IC50 value of just 1.19 µM. In a further development, trifluoromethyl susbstituted nitrobenzene (photoinduced NO donor) moiety was attached to ebselen to release NO under photoirradiation and scavenge peroxynitrite. These two compounds can be considered as potential therapeutic candidates for disease conditions, where the NO bioavailability is compromised with an increase in the peroxynitrite levels. | en_US |
