published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Physics / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

No description available.

No description available.

The main goals of this research were to synthesize nitrogen oxide releasing diazeniumdiolates and their prodrugs and to evaluate their pharmacological effects. The different projects and their results are described below. i. Comparison of HNO and NO donating properties of cyclic amine diazeniumdiolates Diazeniumdiolates are an attractive class of donor compounds as they can be tuned to release NO or both NO and HNO depending upon the amine backbone. Isopropylamine (IPA/NO) and cyclohexylamine (CHA/NO) diazeniumdiolates are currently the only examples of primary amine based diazeniumdiolates. A series of structurally related cyclic amine based diazeniumdiolates were synthesized and characterized. An acetoxymethyl derivative was also synthesized to facilitate cellular uptake and to achieve higher HNO levels in cells. ii. Nitrogen oxide releasing diazeiumdiolate based adducts of N-des-methyl-tamoxifen Nitrogen oxide (NO/HNO) donating diazeniumdiolate adducts of N-desmethyltamoxifen (a key metabolite of the breast cancer drug tamoxifen) were synthesized. DEA/NO-AcOM, an NO donor was also synthesized to monitor the effect of NO on breast cancer cell survival. Derivatives of N-desmethyltamoxifen were found to be effective towards estrogen receptor positive (ER+) cells only. DEA/NO-AcOM was found to be cytotoxic towards estrogen-dependent and independent cell lines, in combination with tamoxifen, or by itself. iii. Synthesis and characterization of nitrogen oxide adducts with non-steroidal anti-inflammatory drugs (NSAIDs) Our group has shown HNO releasing diazeniumdiolate derivatized aspirin to be comparably effective in preventing gastric ulceration to NO-releasing diazeniumdiolate based aspirin analogues. Series of such NSAID adducts were further extended by synthesizing such derivatives of indomethacin and niflumic acid. NO/HNO releasing analogues of aspirin and indomethacin were cytotoxic towards two different breast cancer cell lines, irrespective of estrogen dependence.iv. Chlorambucil analogue of PABA/NOChlorambucil, an alkylating agent is used in leukemia treatment. Tumor cells resistant to alkylating agents often have increased glutathione levels and increased activity of glutathione-S-transferase (GST). PABA/NO is an NO donor with a promising anticancer profile. The chlorambucil analogue of PABA/NO was synthesized to utilize GST for releasing NO and to potentially overcome cellular resistance.

Interactions between certain fuel sulfur compounds and nitric oxide (NO) in turbulent gaseous and distillate oill diffusion flames were experimentally investigated utilizing a 75,000 Btu/hr laboratory combustor. Aerodynamics, air preheat conditions, and overall excess air conditions were varied to determine their role on any such interaction. Results indicated that addition of sulfur dioxide (SO₂) to natural gas flames could enhance or inhibit NO emissions. Local flame stoichiometry and temperature, which were influenced by fuel injector type, determined which effect was observed and the extent to which it occurred. Thiophen (C₄H₄S) and pyridine (C₅H₅N) were added to #2 diesel oil to determine effects of fuel sulfur on conversion of chemically bound fuel nitrogen to No. No discernible effect was observed at "zero" air preheat conditions. No emissions were enhanced at high air preheat conditions. Addition of SO₂ to natural gas flames doped with ammonia (NH₃) produced a significant increase in conversion of NH₃ to NO at high air preheat conditions. Inhibition effects were explained in terms of homogeneous catalysis of recombination reactions by SO₂. Hydrogen abstraction reactions involving reduced sulfur species and other oxidation reactions involving SO₂, or a reduced form, were considered to explain the enhancement effect.

The gaseous messenger, nitric oxide (NO), has emerged as a key component of olfactory systems. Localization and imaging studies in the moth, Manduca sexta, suggest that NO may affect the excitability of olfactory neurons by modifying neuronal membrane properties through sGC-dependent mechanisms. This hypothesis was tested using a multidisciplinary approach, including two types of physiological recording techniques and immunocytochemical analysis of sGC antibody expression in the Manduca brain. The excitability of large populations or individual antennal lobe (AL) neurons was monitored with in vivo physiological recordings while various NO pharmacological agents were bath applied to the brain. To examine possible targets of NO, the binding site of sGC was blocked and the results were compared to NO blockade. Finally, sGC immunocytochemistry was used to also determine possible targets of NO.Two NO synthesis inhibitors and a sGC blocker were potent effectors of resting, baseline activity in the Manduca brain. Blocking NO synthesis caused significant decreases in AL neuron conductance. This conductance decrease led to changes in baseline activity, including the appearance of bursts in some neurons, and increased and decreased firing rates in other neurons. Further, the neurons had a decreased responsiveness and excitability to presynaptic input. Blocking the sGC binding site caused similar effects in most neurons, which indicates that NO likely acts through sGC-dependent signaling to exert its effects in at least a subset of neurons. However, some neurons had different responses to NO and sGC blockade, which indicates that NO may act through other signaling mechanisms in some neurons. Further examination using sGC immunocytochemistry revealed that only about 90% of projection neurons (PNs) and 30% of local neurons (LNs) contained sGC immunoreactivity.The results in this dissertation indicate that NO performs a global function in the antennal lobe to maintain the resting membrane conductance of AL neurons. NO likely exerts its effects through both sGC-dependent and sGC-independent mechanisms. Finally, these results have major implications for odor coding in all species, as NO has been found in the olfactory systems of every animal examined thus far.