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<p> Since first being proposed as a biological oxidant in 1990 by Beckman¹, the understanding of peroxynitrite&rsquo;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^nd order rate constants is also illustrated.</p>

Further studies on the amine directed hydrocarboxylation are presented. Hydrocarboxylation of (N-(2-butyl-3,3-dideutero)-4-pentenyl-n-butylamine) carbonyl rhodium chloride gave rise to 1-butyl-3-methyl-4,4-dideutero-5-butyl-2-piperidinone exclusively in 71% yield with no evidence of deuterium scrambling. This result strongly suggests that the hydrocarboxylation does not proceed through a $\pi$-allyl rhodium complex. The diastereoselectivity of the formation of Rh(I) complexes was influenced by alkene geometry, amine substituents and a chiral group on nitrogen. Steric interactions in the Rh(I) complexes account for the diastereofacial selectivity of the coordination of the alkene to the rhodium. / Investigations were performed on approaches to the stereoselective synthesis of corynantheidol. Studies towards the preparation of cis 3,4-disubstituted piperidinone key intermediates indicated that reaction of cis bishomoallylic amines with (Rh(CO)$\sb2$Cl) $\sb2$ or (Rh(CO)(ethylene)Cl) $\sb2$ did not give rise to Rh(I) complexes and oxygen functionalities in the olefin amines hindered the hydrocarboxylation of Rh(I) complexes. Cis-3-ethyl-4-(3-methyl-2-butenyl)-2-piperidinone which was a suitable key intermediate for synthesis of corynantheidol was obtained with high diastereoselectivity, but in modest yield. Attempts to hydrocarboxylate of Rh(I) complexes with a number of ligands on nitrogen are also described. / Source: Dissertation Abstracts International, Volume: 55-04, Section: B, page: 1445. / Major Professor: Marie E. Krafft. / Thesis (Ph.D.)--The Florida State University, 1994.

The binding of bis(1,10-phenanthroline)Cu(I)$\sp{+}$, Phen$\sb2$Cu$\sp{+}$, to DNA was investigated. Biochemical and physical techniques were employed to determine (1) the sequence preferences for binding, (2) the properties of the DNA macromolecule responsible for the binding preferences, and (3) the equilibrium binding constant and the mode of binding. / Binding specificity was primarily at the level of triplets and quartets. The trimer TAT was consistently the most preferred sequence with strong cleavage occurring at the central adenosine. The trimer, TGT, and the tetramer sequences, TAGT, CAGT, and TAAT, were moderately to strongly preferred. Preferential cleavage was also observed for the pentamer CAAGC. / An oligonucleotide duplex containing TAT was strongly cleaved at the central adenosine. Duplexes containing C(:G)AT, TGT, TAC(:G), and TAC(:I) all showed significantly reduced cleavage. Duplexes containing C(:I)AT and TIT were cleaved at level nearly equivalent to that for the TAT duplex. These results support a favored intercalation site at TA steps as the primary determinant of Phen$\sb2$Cu$\sp{+}$ preferential binding with inhibition arising due to guanine amino groups in the minor groove. / The mono-complex, PhenCu$\sp{+}$, preferentially cleaved at CG sequences and not at TA sequences, indicating a crucial role in specificity determination for the non-intercalated phenanthroline. Inhibition of cleavage by guanine 2-amino groups can then be attributed to unfavorable contacts with the protons at the 2 and 9 positions of the non-intercalated phenanthroline. / An induced, conservative circular dichroism spectrum and increases in the viscosity of DNA solutions upon addition of Phen$\sb2$Cu$\sp{+}$ confirmed intercalation as the mode of binding. From visible spectroscopy studies an equilibrium binding constant on the order of 10$\sp4$ at 0.2 M ionic strength was determined. Binding was observed to be positively cooperative and dependent upon the concentration of uncomplexed phenanthroline in solution. Cooperative binding can be attributed to the need to distort the complex from its preferred geometry upon intercalation with subsequent favorable structural rearrangement of the DNA helix after binding. / Source: Dissertation Abstracts International, Volume: 51-01, Section: B, page: 0195. / Major Professor: Randolph L. Rill. / Thesis (Ph.D.)--The Florida State University, 1989.

A series of lacunary (XM$\sb{11}$O$\sb{39}\sp{\rm n-}$ and P$\sb2$M$\sb{11}$O$\sb{61}\sp{10-}$) and plenary (SiW$\sb{12}$O$\sb{40}\sp{4-}$ and P$\sb2$M$\sb{18}$O$\sb{62}\sp{6-}$) polyoxometalates (POM) were synthesized, analyzed and their solution chemistry with lanthanide cations was studied by a variety of physical methods. These lanthanide complexes are evaluated with regard to potential applications as magnetic resonance imaging agents. / For elemental analysis of POM, quantitative methods were developed using ICP-AES for the determination of B, Si, Ge, P and Mo and atomic absorption spectroscopy for Na. The two-step procedure minimizes interelement interferences using matrix matching of sample and standard solutions, offering comparable precision to classical methods. The FTIR spectra of POM in D$\sb2$O and in KBr demonstrated their aqueous stability, and provided evidence of similarities between the solution and solid state structures. / The thermodynamics parameters of complexation ($\Delta$G, $\Delta$H, and $\Delta$S) of Eu(III) with POM were studied at 1 M ionic strength. pK$\sb{\rm a}$ values for the lacunary POM indicate weak basicity with two protonations between pcH 7 and 2. $\sp7$F$\sb0 \to \ \sp5$D$\sb0$ Selective excitation spectra coupled with the computer program, SQUAD, were used to determine 1:1 and 1:2 stability constants and to calculate $\Delta$G$\sb{\rm 10n}$ (n = 1,2). The stability constants are discussed in terms of statistical, electrostatic and geometrical effects. The enthalpies of complexation, $\Delta$H$\sb{\rm 10n}$ (n = 1,2), were determined for the formation of the 1:1 and 1:2 complexes of Eu(III) by titration calorimetry. The entropies of complexation, $\Delta$S$\sb{\rm 10n}$ (n = 1,2), were calculated from $\Delta$G$\sb{\rm 10n}$ (n = 1,2) and $\Delta$H$\sb{\rm 10n}$ (n = 1,2) values. / In addition, the $\sp7$F$\sb0 \to \sp5\rm D\sb0$ selective excitation spectra of Eu(III)-polyoxometalate complexes were evaluated qualitatively. Based on the number of peaks, the number of inner sphere H$\sb2$O molecules and the known structures, binding sites were proposed for 1:1 and 1:2 complexes. / The Gd(POM)$\sb2$ complexes were kinetically unstable in Sprague-Dawley rat serum. In vitro challenges to Gd(POM)$\sb2$ by metal cations, DTPA, and DTPA-doped serum suggest instability in serum is due primarily to a transmetalation mechanism. / Source: Dissertation Abstracts International, Volume: 56-04, Section: B, page: 2008. / Major Professor: Gregory R. Choppin. / Thesis (Ph.D.)--The Florida State University, 1995.

A re-examination of the reactions of (Z)-2,3:5,6-bis-O-(1-methylethylidene)-N-(phenylmethylidene)-$\alpha$- scD-mannofuranosylamine N-oxide and (Z)-2,3:5,6-bis-O-(1-methylethylidene)-N-(phenylmethylidene)-$\beta$- scD-gulofuranosylamine N-oxide with methylmagnesium bromide was undertaken to determine why the former gave the addition product in low yield and only moderate stereoselectivity, while the latter proceeded in high yield and with high stereoselectivity. A mechanism was proposed to explain the differences and three additional benzaldehyde nitrones bearing chiral auxiliaries derived from scD-lyxose were examined. The key interaction was indicated to be the formation of a chelated structure between the oxygen at C(5), the furanosyl oxygen and a magnesium atom. N-Glycosylnitrones that could form the chelate gave the corresponding N-hydroxy-$\alpha$-methylbenzenemethanamine after hydrolysis of the chiral auxiliary in high yield with high stereospecificity. / Pretreatment of the N-glycosylnitrones with TMSCl (2-5 equiv; 0$\sp\circ$C) prior to the addition of methylmagnesium bromide ($-$78$\sp\circ$C) afforded after hydrolysis, N-hydroxy-$\alpha$-methylbenzenemethanamine with the opposite configuration from the one in the absence of TMSCl. / In addition to benzaldehyde nitrones, N-glycosylnitrones derived from aliphatic aldehydes were shown to undergo diastereospecific addition of methylmagnesium bromide to give the corresponding N-hydroxy-$\alpha$-methylalkylamines in good yield with high ee. The absolute configuration of the product was also reversed upon pretreatment with TMSCl. / Intramolecular versions of this process were attempted. The N-methylnitrone of 3-(2-iodophenyl)propanal reacts smoothly with $\sp t$BuLi at $-$78$\sp\circ$C to give N-hydroxy-N-methyl-1-aminoindane in 92% yield. However, analogous reaction of the corresponding N-glycosylnitrone afforded the cyclic hydroxylamine in only 8.7% ee. Finally, initial attempts to achieve stereospecific carbon-carbon bond formation by radical addition to N-glycosylnitrones failed. / Source: Dissertation Abstracts International, Volume: 56-01, Section: B, page: 0247. / Major Professor: Martin A. Schwartz. / Thesis (Ph.D.)--The Florida State University, 1994.