Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 September 30

The nicotinic cholinergic receptor protein of the fish electric organ, Torpedo fuscomaculata, has been isolated, purified and shown to represent a true model for the nAChR from other species and higher vertebrates. It is an integral membrane protein composed of four different subunits, tightly associated with other functional, but non-specific proteins. Purification of the nicotinic cholinergic receptor by chromatofocusing demonstrates an improved method over that of affinity and ion-exchange chromatography. Gel chromatography and SDS-polyacrylamide gel electrophoresis show evidence of four subunits; a(40-44 kDa), 6(53 kDa ),'Y(63 kDa) and 6(66 kDa) despite some degradation of receptor molecules by intracellular proteases. Spectrophotometric and fluorimetric studies of receptor-ligand interactions, show the functional and chemical integrity of the receptor to remain intact after solubilisation. The effect of cholinergic ligands on purified receptor preparations indicate quenching of the intrinsic fluorescence of the receptor. Agonists, like acetylcholine, bind and cause local conformational transitions, changing the active region from a hydrophobic to a hydrophilic environment. This phenomenon is illustrated by the 10-fold increase in fluorescence when the receptor is in a desensitised state. Antagonists, such as d-Tubocurarine, block this conformational transition. In vitro rectus abdominis muscle preparations . show the nitrosamines, dimethylnitrosamine and diphenylnitrosamine, to be true agonists of the nAChR. However their low affinity and specificity for the receptor precludes them as photoaffmity labelling agents. Photoactivation of dimethylnitrosamine occurs when associated with an acidic hydrogen at the active site of the receptor, suggesting energy-transfer labelling to be more facile than photoaffmity labelling. The membrane-bound receptor, in the presence of these nitrosamines, undergoes conformational transitions regulating the opening and closing of the ion-channel. Desensitisation and receptor activation are shown to involve one and the same molecular transition.

The coordination behaviour of 4-aminoantipyrine (H2pap) and its Schiff base derivatives with the oxorhenium(V) and tricarbonyl rhenium(I) cores are reported. The reactions of trans-[ReOX3(PPh3)2] (X = Cl, Br) with H2pap were studied, and the complexes cis-[ReX2(pap)(H2pap)(PPh3)](ReO4) were isolated. The ligand pap is coordinated monodentately through the doubly deprotonated amino nitrogen as an imide, and H2pap acts as a neutral bidentate chelate, with coordination through the neutral amino nitrogen and the ketonic oxygen. The reactions of trans-[ReOBr3(PPh3)2] and cis-[ReO2I(PPh3)2] with -(2-aminobenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (H2nap) and 4-(2-hydroxybenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (Hoap) are also reported. The complexes cis-[Re(nap)Br2(PPh3)]Br, [ReO(OEt)(Hnap)(PPh3)]I and [ReO(OMe)(oap)(PPh3)]I were isolated and structurally characterized. The reactions of the Schiff base derivatives 1,2-(diimino-4’-antipyrinyl)ethane (dae) and 2,6-bis(4-amino-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one)pyridine (bap) with [Re(CO)5X] (X = Br or Cl) produced fac-[Re(CO)3(dae)Cl] and fac-[Re(CO)3(bap)Br] respectively. A series of rhenium(I) tricarbonyl complexes containing bidentate derivatives of aniline was synthesized and structurally characterized. With 1,2-diaminobenzene (Hpda) the ‘2+1’ complex salt fac-[Re(CO)3(κ1-Hpda)(κ2-Hpda)]Br was isolated, but with 2-mercaptophenol (Hspo) the bridged dimer [Re2(CO)7(spo)2] was found. The neutral complex [Re(CO)3(ons)(Hno)] was isolated from the reaction of [Re(CO)5Br] with 2-[(2-methylthio)benzylideneimino]phenol (Hons; Hno = 2-aminophenol), with ons coordinated as a bidentate chelate with a free SCH3 group. In the complex [Re(CO)3(Htpn)Br] (Htpn = N-(2-(methylthio)benzylidene)benzene-1,2-diamine) the potentially tridentate ligand Htpn is coordinated via the methylthiol sulfur and imino nitrogen atoms only, with a free amino group. These rhenium(I) complexes, with the exception of [Re2(CO)7(spo)2], revealed broad emissions centred around 535 nm. The reactions of the rhenium(V) complex cis-[ReO2I(PPh3)2] with 2-aminothiophenol (H2atp), benzene-1,2-dithiol (H2tdt) and 2-hydroxybenzenethiol (H2otp) led to the formation of the rhenium(III) compounds [Re(Hatp)(ibsq)2].OPPh3, [Re(sbsq)3].OPPh3 and [Re(obsq)3].OPPh3 (ibsq = 2-iminothiobenzosemiquinonate, sbsq = 1,2-dithiobenzosemiquinonate, obsq = 2-hydroxothiobenzosemiquinonate) respectively. The complexes adopt a trigonal prismatic geometry around the rhenium centre with average twists angles between 3.20-26.10˚. The E1/2 values for the Re(III)/Re(IV) redox couple were found to be 0.022, 0.142 and 0.126 V for [Re(Hatp)(ibsq)2].OPPh3, [Re(sbsq)3].OPPh3 and [Re(obsq)3].OPPh3 respectively. The reactions of the benzoxazole ligands, 3-(benzoxazol-2-yl)pyridin-2-ol (Hbop) and 5-amino-2-(benzoxazol-2-yl)phenol (Habo) with a [ReO]3+ precursor led to the rhenium(III) complex, [ReCl2(bop)(PPh3)2], and the complex salt, [ReO(abo)I(PPh3)2]ReO4, respectively. A variety of benzothiazole and benzimidazole derivatives were reacted with [Re(CO)5Br]. In the case of bis(benzothiazol-2-ylethyl)sulfide (bts), the neutral complex fac-[Re(CO)3(bts)Br] was obtained. The dimeric complexes (μ-dbt)2[Re(CO)3]2 and (μ-mbt)2[Re(CO)3]2 were formed when 1,3-bis(benzothiazol-2-yl)thiourea (Hdbt) and 1-(benzothiazol-2-ylidene)-3-methylthiourea (Hmbt) were used as ligands. The reaction of 2,2’-(oxybis(methylene))bis(benzimidazole) (bmb) with [Re(CO)5Cl] resulted in the rhenium(I) complex salt fac-[Re(CO)3(bmb)]+, with the tri-μ-chlorohexacarbonyl dirhenate [Re2(CO)6Cl3]- as the counter anion. The neutral complex fac-[Re(CO)3(btp)Cl] was isolated from the reaction of the 2,9-bis(benzothiazol-2-yl)-1,10-phenanthroline (btp) ligand and [Re(CO)5Cl]. The reactions of trans-[ReOCl3(PPh3)2] with bis(benzimidazol-2-ylethyl)sulfide (btn) and 1-(benzothiazol-2-ylidene)-3-methylthiourea (Hmbt) led to the formation of the cationic compounds (μ-O)2[Re2O2(btn)2]I2 and [ReCl2(bte)(PPh3)2]Cl (bte = (benzothiazole-2-yl)-N-ethylidenemethanamine) respectively.

M.Sc. (Chemistry) / Please refer to full text to view abstract

Malaria remains one of the greatest problems facing developing nations, especially in sub-Saharan Africa. Part of the problem stems from increased resistance to current treatments hence there is a large drive to develop novel antimalarial compounds. Several chelating compounds, including 8-hydroxyquinoline (8-HQ), 1,10- phenanthroline (1,10-phen) and 2,2.6,2-terpyridine (terpy), have disputed activities (8-HQ and 1,10-phen) or are untested (terpy). Furthermore the mechanism(s) by which these ligands and/or their complexes with metal ions exhibit their toxic effect is unknown. In order to resolve these issues, a study of the antimalarial activities of the free ligands, the ligands complexed with metal ions (Au 3+, Cu 2+, Fe 3+, Pd 2+ and Pt 2+), and the ligands with free metals in solution were measured. The ligands, complexes and metals were also tested for their ability to inhibit β-haematin formation, the mode of action ascribed to the most widely used antimalarial, chloroquine. The background toxicity levels of the various metal ions (previously unreported) were also measured and are reported here. None of the ligands were found to have particularly high activity (all approximately 1μM). In general the metals in were found to have no beneficial effect on activity whether complexed or freely available in solution. None of the ligands were found to inhibit β-haematin formation. The complexes however, with the exception of those of Cu 2+, all inhibited β-haematin formation. Upon further investigation it was found that the each of the metal ions with the exception of Cu 2+ had an innate ability to inhibit β-haematin formation. Thus the mode of action of the ligands and the complexes is likely to be via different mechanisms. In an attempt to enhance the activities of the ligands they were modified by covalently linking them to nutrients essential to the malaria parasite (adenosine and pantothenic acid). These six novel compounds however, showed no improvement in action. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2008.

Thesis (Ph. D.)--University of Akron, Dept. of Chemistry, 2009. / "May, 2009." Title from electronic dissertation title page (viewed 11/25/2009). Advisor, Michael J. Taschner; Committee members, David Modarelli, Jun Hu, Wiley J. Youngs, Amy Milsted; Department Chair, Kim C. Calvo; Dean of the College, Chand Midha; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

Thesis (M.S.)--University of North Carolina at Wilmington, 2004. / Includes bibliographical references (leaves : [63]-65).

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Thesis (Ph.D.)--McMaster University, 2002. / Adviser: Maria Rozakis-Adcock. Includes bibliographical references. Also available via World Wide Web.