Thesis (M.S.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 140-168) Also available in print.

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Class of 2011 Abstract / OBJECTIVES: To evaluate the quality of evidence in the literature substantiating major drug-drug interactions of the macrolide antibiotics azithromycin, clarithromycin, and erythromycin with digoxin, ergot alkaloids, and pimozide. METHODS: In this descriptive retrospective analysis, a list of articles reporting on each drug-drug interaction was compiled from the online databases Medline and International Pharmaceutical Abstracts, and the drug compendia Micromedex and Facts & Comparisons. The studies included in this analysis were primary literature reports, written in English, and consisted of human subjects. All studies included were evaluated using a 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions (van Roon scale). This scale rates the study type from lowest to highest quality, from zero to four. Case reports were additionally analyzed using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. RESULTS: Thirty-seven studies met the selection criteria. There were 28 studies involving digoxin, two studies involving pimozide and seven studies involving ergot alkaloids. The mean quality of evidence score on the van Roon scale was 2.3 + 0.75, where digoxin studies had a score of 2.3 + 0.74, ergot alkaloids had a score of 1.9 + 0.38 and pimozide only had two studies with evidence scores of 2 and 4. Sixty-two percent of the studies reviewed were case reports. CONCLUSION: The reports substantiating some drug-drug interactions may be of low quality and few in number.

A number of 14-membered lactones, derived from 42 or 43 were used to investigate a series of alkylation, hydride reduction and hydrogenation reactions. These reactions yielded diastereoselective product distributions which were rationalized as proceeding through a [3434] conformation. A simple model for determining these low energy conformations was developed using MM2 calculations, energy trends of acyclic molecules, X-ray crystallography and NMR spectroscopy. In order to unambiguously identify ring conformations, a method to generate polar maps of the large ring lactones was developed. These polar maps quickly differentiated complex ring conformations as well as identifying the symmetry elements of a conformation. With the aid of polar maps, a new solid state conformation for 14-membered rings was discovered for two macrolides synthesized in this project. Furthermore, three additional unidentified examples of this conformation were recognized from the literature. Energy calculations showed this twisted conformation to be of very low energy. The discovery of the twist conformation led to an improved nomenclature for large rings which considers the number of bonds separating both corner and pseudo corner atoms. Under this proposed nomenclature, the twist conformation was designated the [34'3'4'] conformation. During this investigation, a useful technique for assigning the stereochemistry of E and Z-trimethylsilyl (TMS) enol ethers was developed using ¹H NMR nuclear Overhauser effect difference spectroscopy (NOEDS) experiments. One advantage of this technique over the widely used ¹³C NMR method is that only one isomer is required to accurately assign the Eor Z. stereochemistry. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

Studies toward synthesis of subunits of sanglifehrin A, an immunosuppressant featuring a highly substituted [5,5]-spirolactam moiety as well as a 22-membered macrocycle are described. The macrolactone contains a peptidic backbone characterized by an unusual [beta]-substituted (S)-piperazic acid and (S)-m-hydroxyphenylalanine units. These studies resulted in the synthesis of advanced intermediate 358 which contains all of the carbon atoms of the C1-C25 macrolactone of sanglifehrin A, and 251 which bears the C31-C41 carbon skeleton of the [5,5]-spirolactam moiety of sanglifehrin A. A Masamune anti-aldol reaction of aldehyde 294 and ester 285 furnished alcohol 295 in a second generation approach to carboxylic acid 242, while a third generation route toward 242 improved the yield and required fewer synthetic steps. An asymmetric, catalytic phase-transfer method was used to introduce an [alpha]-amino function into 331 in the synthesis of (S)-m-hydroxyphenylalanine derivative 244. Assembly of 244, piperazic acid 113 and L-valine derivative 336 into tripeptide 241 using a racemization-free peptide coupling method is described. The synthesis of C31-C37 aldehyde 253 exploited double asymmetric crotylation to set in place the correct configuration of alternating hydroxyl and methyl groups at C33, 34, 35 and 36. / Graduation date: 2013

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Thesis (Ph. D.)--Rutgers University, 2007. / "Graduate Program in Computational Biology and Molecular Biophysics." Includes bibliographical references (p. 86-94).

Thesis (Ph. D.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains ix, 219 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 212-219).