Nitric oxide (NO) has become a molecule of interest in biological research. NO is generated via the oxidation of L-arginine, by NO synthase (NOS), and plays a key role in many bioregulatory systems, including smooth muscle relaxation, platelet inhibition, neurotransmission, and immune stimulation, primarily through the formation of cGMP. N-Diazeniumdiolates (NONOates) are an interesting class of compound that can deliver NO specifically to a target site, with potential biological or therapeutic value and minimal side effects. The versatility of NONOates makes them ideal for studying NO in many different scenarios. Primary amine diazeniumdiolates such as isopropyl amine (IPA/NO) can release HNO under physiological conditions.\\Quantitative Structure Activity/Property Relationships (QSAR/QSPR) relate the structure of a compound, to a property/activity of interest ( biological activity). QSAR/QSPR studies are of great importance in drug design. Model that predict the half-lives of NONOates was built and were studied the influence of each variable on decomposition rate. External validation of this model will be made using new set of NONOates to test the Model.

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Nitroglycerin and isoamyl nitrate have been used as nitrovasodilators since the nineteeth century. However, not until recently has it been known that these compounds were useful since they promoted the release of NO in the body. More recently, a new class of drugs, NO donors, has been developed. These include S-nitrosothiols (RSNO), sydnonimines, and nucleophilic NO adducts.

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.

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