Thesis (M.S.)--Ohio University, June, 2004. / Includes bibliographical references (p. 103-106).

Thesis--University of California, Berkeley, 1959. / "Biology and Medicine" -t.p. "TID-4500 (15th Ed.)" -t.p. Includes bibliographical references (p. 109-113, 156-158).

Thesis (M.S.)--Ohio University, June, 2004. / Title from PDF t.p. Includes bibliographical references (p. 103-106)

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this study is to determine if propoxyphene and norpropoxyphene are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanismbased inhibition is a type of irreversible inhibition that results from an inhibitor or its metabolite binding to an enzyme during drug metabolism, which renders the enzyme nonfunctional. Propoxyphene is an analgesic that is frequently prescribed in the United States and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes. Time-dependent and concentration-dependent loss of activity of CYP3A was measured by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5), and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with vi CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver microsomes fall within the range of reported therapeutic blood levels of propoxyphene, with reversible inhibition constants (Ki values) above therapeutic blood concentrations for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels, except for blood levels after repeated dosing of propoxyphene at high concentrations. The predicted change in the area under the plasma concentration versus time curve of an orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times higher with co-administration of propoxyphene based on in vitro kinetic parameters. Propoxyphene and norpropoxyphene may cause adverse events when chronically administered at high doses and/or when co-administered with other CYP3A substrates.

No description available.

No description available.

Part I of this thesis describes the synthesis of dehydro - perloline ( 3 ), a non basic material obtained from the degradation of the alkaloid perloline ( 1 ), the major alkaloid of New Zealand rye grass. Since a crucial reaction in this sequence involved a Schmidt reaction of fluorenols 4 or 5, some of the mechanistic aspects of this reaction have been investigated. Part II describes the synthesis of caprolactam derivatives 7 with the aim at finding new antagonists or analogues of the CNS inhibitory transmitter, gamma - aminobutyric acid ( GABA ). In Chapter 1, the synthesis of N - alkyl and N - arylcaprolac - tams is described. In Chapter 2, the synthesis, by several methods, of simple 3 - alkylcaprolactams is investigated. Chapter 3 describes synthetic methods for the preparation of 4 - substituted caprolactams. Chapter 4 presents the preparation of 5 - alkyl and 7 - alkyl - caprolactams by the Schmidt reaction on 4 - alkyl and 2 - alkylcyclo - hexanones. Chapter 5 describes some investigations of possible syntheses of 6 - alkylcaprolactams. Chapter 6 contains the results of testing of some lactams and thiolactams as well as their structure - activity relationships. / Thesis (Ph.D.)--Department of Organic Chemistry, 1976.

The emergence of multi-drug resistance (MDR) to antimalarial and anticancer drugs has stimulated a search for novel MDR inhibitors/reversers. Bisbenzylisoquinoline alkaloids (BBIQ) are potential agents for reversing MDR, especially when used as synergistic enhancers of anticancer and antimalarial drugs with improved therapeutic efficacy. Despite numerous useful biological activities reported for BBIQ’s, the various syntheses of individual members remained cumbersome and the overall yields are low. In addition, published methods are nonstereospecific and produced racemates. The aim of this project was to develop a synthetic pathway for the preparation of cycleanine, a natural BBIQ with a symmetrical structure. The protocols developed for the synthesis of cycleanine will serve as a template for the synthesis of other BBIQ’s with more complex structures. The only published total synthesis of cycleanine did not address regioselectivity and stereoselectivity, furthermore, key steps suffered from extremely low yields of the products. Our synthetic pathway is a chiral auxiliary-based asymmetric synthesis that generates enantioselectively a 1,2,3,4-tetrahydroisoquinolines (THIQ) monomers. Cheap, commerciallyavailable starting materials were used to prepare monomers in a regioselective as well as stereoselective manner in good yields. The key feature of this method entails coupling of a chiral β-phenethylamine and halophenylacetaldehyde using the Pictet-Spengler reaction. Due to the difficulties encountered during the course of the preparation of monomers, different methods were tried and formation of unanticipated products rationalised. Dimeric BBIQ’s are constituted of monomeric THIQ’s which are reported to have array of biological properties including MDR reversing activities, therefore, the total synthesis of cycleanine will serve two purposes. In this investigation, the THIQ monomers were synthesised by a pathway that avoid harsh reaction conditions. Major reactions employed include nucleophilic aromatic substitutiton, Wittig reaction, hydroboration and IBX oxidation. Some of the steps were attempted on model compounds to optimise the conditions prior to attempting the reaction on cycleanine precursors. Two major contributions toward the synthesis of BBIQ’s were made in this study. The reaction conditions to control the regioselectivity and enantioselectivity of the Pictet- Spengler reaction for the preparation of THIQ moiety were developed. A major drawback of the published syntheses of BBIQ’s is the harsh conditions and low yields associated with the Ullmann reaction, which is used in the formation of the diaryl ether bonds. We have shown that the microwave-assisted nucleophilic aromatic substitution of aryl fluorides provide a much superior method for the formation of the key diaryl ether bond. Although we failed to form the final diaryl ether bond, the pitfalls encountered in the synthetic pathway are discussed and potential solutions are presented. The developed synthetic pathways are of general applicability and therefore can also be employed in the synthesis of other macrocyclic natural products containing diaryl ethers. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.

Part I of this thesis describes the synthesis of dehydro - perloline ( 3 ), a non basic material obtained from the degradation of the alkaloid perloline ( 1 ), the major alkaloid of New Zealand rye grass. Since a crucial reaction in this sequence involved a Schmidt reaction of fluorenols 4 or 5, some of the mechanistic aspects of this reaction have been investigated. Part II describes the synthesis of caprolactam derivatives 7 with the aim at finding new antagonists or analogues of the CNS inhibitory transmitter, gamma - aminobutyric acid ( GABA ). In Chapter 1, the synthesis of N - alkyl and N - arylcaprolac - tams is described. In Chapter 2, the synthesis, by several methods, of simple 3 - alkylcaprolactams is investigated. Chapter 3 describes synthetic methods for the preparation of 4 - substituted caprolactams. Chapter 4 presents the preparation of 5 - alkyl and 7 - alkyl - caprolactams by the Schmidt reaction on 4 - alkyl and 2 - alkylcyclo - hexanones. Chapter 5 describes some investigations of possible syntheses of 6 - alkylcaprolactams. Chapter 6 contains the results of testing of some lactams and thiolactams as well as their structure - activity relationships. / Thesis (Ph.D.)--Department of Organic Chemistry, 1976.