Thesis (M.S.)--University of North Carolina at Greensboro, 2007. / Title from PDF title page screen. Advisor: Jason J. Reddick; submitted to the Dept. of Chemistry and Biochemistry. Includes bibliographical references (p. 122-124).

Thesis (M.S.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains vii, 87 p. : ill. Includes abstract. Includes bibliographical references.

The effect of inducing agents of cytochrome P-450 on the binding and metabolism of three local anaesthetic agents: lidocaine, mepivacaine and bupivacaine has been investigated. All three local anaesthetic agents bound to the type I binding site of cytochrome P-450, which is characteristic of substrate binding to cytochrome P-450, and stimulated the CO-inhibitable oxidation of NADPH. Lidocaine is shown to be metabolized by cytochrome P-450 to the products MEGX and acetaldehyde. The forms of cytochrome P-450 elevated with phenobarbital and/or pregnenolone-16α-carbonitrile were shown to play an important role in the binding of lidocaine to cytochrome P-450. Cytochrome P-448 did not appear to be involved in the binding of lidocaine to cytochrome P-450. These findings are supported by the ability of the inhibitors of cytochrome P-450 viz. metyrapone, SKF 525-A and CO:O₂ to inhibit binding of lidocaine to cytochrome P-450. No single form of cytochrome P-450 appears to preferentially metabolize lidocaine, but rather multiple forms of the enzyme appear to be involved in the metabolism of lidocaine. The phenobarbital inducible form of cytochrome P-450 appears to play a major role in the binding of mepivacaine to cytochrome P-450. Cytochrome P-450 in microsomes from rats pretreated with β-naphthoflavone and pregnenolone-16α-carbonitrile does not appear to have a significant role in the binding of mepivacaine to cytochrome P-450. All forms of cytochrome P-450 are involved in the metabolism of mepivacaine· to metabolic products as assessed by the oxidation of NADPH. However, the form of cytochrome P-450 induced by pretreatment of rats with phenobarbital may play a predominant role in the total metabolism of mepivacaine. Multiple forms of cytochrome P-450 appear to be involved in the binding and total metabolism of bupivacaine. As in the case of mepivacaine, the total metabolism of bupivacaine, as assessed by the oxidation of NADPH, may be predominantly catalyzed by the form of cytochrome P-450 found in microsomes from rats pretreated with phenobarbital. Partially purified cytochrome P-450 was found to bind lidocaine in a type I manner and, in the presence of the artificial electron donor H₂O₂, produce MEGX. This further supports the role of cytochrome P-450 in the in vitro metabolism of lidocaine. Hepatocytes were found to metabolize lidocaine to MEGX, indicating that lidocaine metabolism in vivo might well be mediated by cytochrome P-450.

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2017-2018 / Les stéroïdes et leurs dérivés constituent une classe biologique unique intervenant dans un grand nombre de processus physiologiques. Ces composés suscitent un fort intérêt thérapeutique, notamment parce qu'ils jouent un rôle crucial dans le développement des cancers hormono-dépendants tels que les cancers du sein et de la prostate. L'approche thérapeutique la plus utilisée consiste ainsi à développer des dérivés stéroïdiens qui vont agir en tant qu'inhibiteurs de certaines enzymes de la stéroïdogénèse, et ce, afin de bloquer la production des androgènes ou des estrogènes selon l'effet souhaité. Néanmoins, l'activité des dérivés stéroïdiens est versatile et ces composés peuvent aussi présenter d'autres intérêts thérapeutiques en agissant sur des cibles biologiques très distinctes. La première partie de ce mémoire est consacrée au développement d’une chimiothèque d’aminostéroïdes similaires au RM-581 (noyau C18-stéroïdien), un analogue du RM-133 (noyau C19-stéroïdien) qui a montré une activité cytotoxique sur une large variété de lignées cellulaires issues de différents cancers. La synthèse sur support solide a été utilisée pour le développement de ces analogues du RM-581. Quarante aminostéroïdes avec différentes chaînes latérales amino-substituées en position C2 du noyau estrane ont ainsi été obtenus. Une activité cytotoxique significative a été observée pour les mêmes composés indépendamment des lignées cancéreuses testées. Un composé a par ailleurs montré une activité anticancéreuse deux fois supérieure à celle du RM-581 et pourrait être un candidat prometteur pour le traitement de plusieurs cancers, dont le cancer du pancréas. La deuxième partie de ce mémoire porte sur le développement d'inhibiteurs de la CYP1B1, une enzyme ayant un rôle mutagène important dans le cadre de certains cancers. À partir d’inhibiteurs connus de cette enzyme, d’études de "docking" et basé sur un criblage de l'inhibition de la CYP1B1 par un large éventail de dérivés stéroïdiens; trois séries d'inhibiteurs C18-stéroïdiens ont été conceptualisées et synthétisés. Les résultats obtenus avec ces composés ont montré que l'introduction d'un groupe aromatique en position C2 d'un noyau 17β-estradiol favoriserait des interactions π-stacking avec la CYP1B1. L'activité inhibitrice de ces composés a été comparée avec l'α-naphthoflavone (ANF), un inhibiteur non stéroïdien connu de la CYP1B1. Certains de ces dérivés stéroïdiens ont montré une activité inhibitrice supérieure à celle de l'ANF et font actuellement l'objet de tests biologiques afin d'appuyer leur utilisation thérapeutique pour le traitement de certains cancers. / Steroids and their derivatives form a single biological class involved in a large number of physiological processes. These compounds have a great therapeutic interest, particularly because they play a crucial role in the development of hormone-dependent cancers such as prostate and breast cancers. The most widely used therapeutic approach consists to develop steroid derivatives that will act as inhibitors of certain steroidogenic enzymes to avoid the production of androgens and estrogens according to the desired effect. However, the activity of steroid derivatives is versatile and these compounds can have other therapeutic interests by acting on very distinct biological targets. The first part of this thesis is focused on the development of a library of aminosteroid similar to RM-581 (C18-steroidal nucleus), and analogue to RM-133 (C19-steroidal nucleus) that showed significant cytotoxic activities on a wide variety of cell lines from different cancers. Solid-phase synthesis was used for the development of these RM-581 analogues. Forty aminosteroids with different amino-substituted side chains at position C2 of an estrane nucleus (mestranol) were thus obtained. Significant cytotoxic activities were observed for the same compounds regardless of the cancer cell lines tested. Moreover, one of these aminosteroid derivatives was found to be twice more active than RM-581 and could be a promising candidate for the treatment of several cancers, including pancreatic cancer. The second part of this thesis is devoted to the development of steroidal inhibitors of CYP1B1, an enzyme playing an important mutagenic role in certain cancers. Based on known CYP1B1 inhibitors, docking studies and on a screening of the CYP1B1 inhibition by a broad range of steroid derivatives, three series of C18-steroidal inhibitors were designed and synthesized. The results obtained with these novel steroidal inhibitors showed that the introduction of an aromatic core at position C2 of the 17β-estradiol nucleus appears to be the best strategy for promoting pi-stacking interactions with CYP1B1. The inhibitory activity of these compounds was compared with α-naphthoflavone (ANF), a known nonsteroidal potent CYP1B1 inhibitor. Some of these steroidal inhibitors have shown a greater CYP1B1 inhibitory activity than ANF and are currently undergoing biological tests to support their therapeutic use for the treatment of certain cancers.

Xiao, Yajie. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 156-190). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains viii, 199 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 176-195).

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 169-182).

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 165-195).

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains xiii, 133 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 110-125).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.