<p> Since first being proposed as a biological oxidant in 1990 by Beckman<sup>1</sup>, the understanding of peroxynitrite’s role in oxidative and nitroxidative stress has rapidly expanded. Peroxynitrite has been shown to react wide a wide variety of biomolecules through both nitration and oxidation events, causing extensive cellular damage. Physiological and biochemical studies have implicated peroxynitrite in a wide range of disease states including cardiac disease, ischaemia/reperfusion injury, cancer, diabetes, and both inflammatory and neuropathic pain. Clearly, compounds that are capable of scavenging peroxynitrite are highly desirable.</p><p> Compounds known to reduce peroxynitrite, primarily Mn(III) and Fe(III) Porphyrin, Corrole and Salen complexes, have been widely described in the literature. Typically these are polycationic complexes which render them highly water soluble and excellent for <i>in vitro</i> laboratory measurements, yet poor candidates for <i>in vivo</i> pharmacology due to poor solubility through the hydrophobic spaces within membranes. In order to develop more ideal drug candidates, with the ultimate goal of oral bioavailability, our group initially synthesized charge shielded, cyclohexyl fused, Mn(III) porphyrin complexes that have demonstrated remarkable results in the animal models of antinociceptive, neuropathic and inflammatory pain, conditions known to be driven by the over production of peroxynitrite. Further investigations by our group have also proven Mn(III) complexes derived from the B,O chelated boron dipyrromethene dyes first reported by Burgess are also highly effective in animal pain models.</p><p> The work herein describes the development of Mn(III) complexes of both porphyrins and bis-hydroxyphenyl dipyrromethenes for the use as pharmacological tools in understanding of the role of peroxynitrite in pain and other diseases. A history of porphyrin chemistry and the development of the charge shielded porphyrin scaffold as a synthetic peroxynitrite reductase is given. Design and synthesis of the newly designed Mn(III) bishydroxyphenyl dipyrromethene based complexes is discussed including their advantages over Mn(III) porphyrins. New synthetic work in creating non-cyclohexyl fused analogues of our prototype compounds through a set of orthogonal, Palladium(0) mediated cross-coupling reaction conditions is presented. As the library of catalyst compounds grew a rapid method for the assay of catalytic activity was sought. The development of a novel <i>in vitro</i> chemical assay is demonstrated and its utility in ranking compounds with regards to their peroxynitrite reductase activity, as well as estimating the 2<sup>nd</sup> order rate constants is also illustrated.</p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:10249951 |
| Date | 28 February 2017 |
| Creators | Kamadulski, Andrew |
| Publisher | Southern Illinois University at Edwardsville |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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