The synthesis of the taxanes derivatives has been the major focus of this research. The efforts made towards the synthesis of these complex and successful drugs for the treatment of cancer have resulted in the development of efficient synthetic strategies. These approaches have arisen mainly from our studies in the carbometallation of propargyl alcohols and the development of stereoselective Lewis acid catalyzed IMDA. The application of these potential synthetic strategies has yielded very significant results. The synthesis of the tricyclic core of the taxanes (2.149) by a novel carbometallation-cycloaddition-RCM sequence was successfully achieved using readily available starting materials and mild reaction conditions. In addition, the versatile carbometallation-cycloaddition sequence allowed the synthesis of AB ring system of taxanes with different functionalities (2.126, 2.111 and 2.128). The construction of a functionalized A ring (2.84) was also accomplished. This intermediate and some of its derivatives were employed to attempt the synthesis of B ring of taxanes by RCM. Additionally, the further functionalization of AB and ABC ring-systems of taxanes was investigated. Unfortunately, the synthesis of a biological active taxane derivative was not possible. In addition, we have studied the in situ carbonyl addition oxy-Cope rearrangement of unsaturated ketones.* *Please refer to dissertation for diagrams.

The EtOH extracts of the leaves of Margraviaceae, a relatively rare Central American vine for which ethnobotanical reports suggested possible anti-anxiety properties, showed significant anti-anxiety activity in animal models for anxiety. Subsequent bioassay-guided fractionation of these extracts yielded an EtOAc active fraction (f1). Further bioassay-directed chromatography of (f1), led to the isolation of betulinic acid (3) as the bioactive constituent in 0.01% of dry weight. Six known pentacyclic triterpenoids [( 1a), (1b), (2a), (2b), ( 4), (5a)], six known flavonoids [(6), ( 7), (8a), (8b), (9), ( 10)], chondrillasterol (11), linolenic acid (12 ) and a porphyrin type compound (13) were also isolated. When (3) was administered at 0.5 mg per kg (possibly less) in a variety of rat and mouse model assays, the activity of (3) was comparable to that of Valium, the most famous member of the benzodiazepines family. Synthetic derivatives of (3) were prepared and evaluated for anti-anxiety activity. Several of the simple esters appear to have ideal properties as new drug Candidates. In particular, betulinic acid methyl ester or methyl betulinate (3a) exhibited anti-anxiety activity superior to (3). The activity profile of (3a) is such that (3a) can be considered a viable drug candidate. An excellent relay synthesis of (3) from another closely related natural product betulin (14), that is abundantly available in Eastern Ontario, was developed. Radioactive 3H-labelled betulinic acid methyl ester ( 3a″) was also prepared in order to facilitate identification of relevant anti-anxiety receptors and the mechanism of action of the compound. This is important since (3) showed no significant binding to any of the 40 anti-anxiety receptors currently implicated in anxiety. Therefore, it appears to act as an anti-anxiety agent via a new mode of action.* In a second project, the active components of a member of the Piperaceae or Pepper family (P. tuberculatum) from Costa Rica, were isolated and their structures characterized as 5,6-dihydropiperlonguminine (25), 5,6-dihydropiperine (26), piperine ( 27) and piperlonguminine (28). Extracts from this neotropical plant had been previously demonstrated by our biology collaborators, Professor Arnason's group, to be strongly insecticidal towards a variety of pests including mosquitoes, earwigs and white grubs. Moreover, the P. tuberculatum extracts were as effective as the well-documented Asian (P. nigrum) and African ( P. guineense) Piper species. Piperamides (25)--(28) were synthesized in sufficient amounts to allow extensive evaluation of their insecticidal properties. Experiments with these piperamides showed that the tertiary and quaternary mixtures have greater-than-additive toxicity compared to single compounds or binary mixtures. That is, these piperamides synergize each other. Compound (25) was the most acutely toxic in mosquito larvae bioassays. The field trials to date indicate a high potential for the development of an effective, relatively inexpensive botanically based insecticide. Radioactive 3H-labelled piperine (27″ ) was also synthesized for toxicokinetic studies. *Please refer to dissertation for diagrams.

The present thesis concentrates on the development of the Prins-Pinacol mediated synthesis of bicyclo[3.3.1]nonanones and its application towards the total synthesis of papuaforin A. In addition, an exploratory study of the oxy-Cope/Claisen/ene cascade reaction and the total synthesis of (+)-isofregenedol are presented. These subjects are divided into four chapters. The first part of this thesis describes the discovery and examination of a novel microwave-induced rearrangement of propargyl vinyl ethers delivering cis-bicyclic unsaturated lactones. The methodological investigation of the Prins-Pinacol rearrangement oriented towards the construction of bicyclo[3.3.1]nonanones is discussed in Chapter 3. The synthesis of various precursors and the optimization of the key step are presented. The reactivity observed for the isopropylidene and benzylidene oxocarbenium precursors is then compared. The effect of the substitution of the alkene moiety and at the ring junction is also examined. The Prins-Pinacol rearrangement of complex Diels-Alder cycloadducts is described last. The fourth chapter depicts the advancement towards the total synthesis papuaforin A. The synthesis of a model compound possessing the bicyclo[3.3.1]nonanone core of the natural product is first presented. The progress towards the actual total synthesis is discussed next. Finally, the application of the gold(I)-catalyzed benzannulation of hydroxyenynes to the de novo synthesis of (+)-isofregenedol is described in Chapter 5.

The biaryl core has been identified by medicinal chemists as a privileged structure in pharmaceutical compounds as it is found in 4.3% of all drugs. For over a century, synthetic chemists have sought new methods for their preparation. Breakthroughs in synthetic catalytic methodology over the past thirty years gave rise to now routine reactions such as the Suzuki and Stille couplings. Unfortunately, the need for pre-activation of both coupling partners makes for wasteful installation and subsequent removal of activating agents. Direct arylation reactions are attractive alternatives to traditional cross-coupling methods, as one of the pre-activated partners is replaced with a simple arene. The organometallic coupling partner is typically replaced as it is the most difficult to prepare. Although the advantages of this approach have made it a popular research topic for more than twenty-five years, no general catalysts exist for this transformation, and in a lot of cases reactivity remains a challenge. This thesis will outline our work in this area of research. First, our efforts toward the development of a general catalyst for the intramolecular direct arylation of aryl halides with simple arenes will be presented. These studies led to the development of three new catalysts for this transformation, affording a process general for aryl chlorides, bromides and iodides. Additionally, mechanistic studies performed on this system have brought to the forefront the concerted metallation-deprotonation mechanistic model for direct arylation. Ultimately, these studies led to the first non-directed intermolecular direct arylation of a simple arene. In a second section, efforts toward the inclusion of pi-deficient heteocycles as a substrate class in direct arylation will be outlined. These studies led to the development of a novel cross-coupling reaction of azine N-oxides with aryl halides. Greater mechanistic understanding, made possible through the use of computational tools, was crucial in extending this methodology to azole N-oxides. Finally, the development of novel direct functionalization reactions with picoline derivatives is described. These substrates are among the first to be suitable for catalyst controlled site-selective functionalization of a sp2 or sp3 C-H bond.

In part I of this thesis are described the structural determinations of sitsirikine, dihydrositsirikine and isositsirikine, three new alkaloids from Vinca rosea Linn. Sitsirikine, C₂₁H₂₆O₃N₂, and dihydrositsirikine, C₂₁H₂₈ O₃N₂, were isolated as an inseparable mixture, which was shown by hydrogenation studies to be comprised of an olefin and its dihydro derivative. The formation of formaldehyde upon ozonisation of the mixture, and of propionic acid in a modified Kuhn-Roth oxidation of dihydrositsirikine demonstrated that, sitsirikine possessed a vinyl group. Both sitsirikine and dihydrositsirikine gave mono-acetates, and the N.M.R. data indicated that primary hydroxyl groups were present in the original alkaloids. A methyl ester function suggested by spectral evidence was established by hydride reduction of dihydrositsirikine to a diol. Since the diol, yielded an acetonide, it was inferred that dihydrositsirikine possessed a β-hydroxy-ester unit. The U.V. spectrum of dihydrositsirikine was characteristic of an indole chromophore, which the mass spectrum showed to be part of a tetrahydro-β-carboline system. Dehydrogenatioh afforded a compound with a flavocoryline-type U.V. spectrum, and this suggested that sitsirikine was a relative of the tetracyclic corynantheine class of alkaloids. This was confirmed by conversion of dihydro-corynantheine into dihydrositsirikine. The structure of the related indole alkaloid isositsirikine, C₂₁H₂₆O₃N₂, was determined by a similar series of reactions. Ozonolysis yielded acetaldehyde, which authenticated the ethylidene group indicated by the N.M.R. spectrum. Acetylation afforded a mono-acetate, whose N.M.R. spectrum suggested that isositsirikine had a primary hydroxyl function. A methyl ester was established by hydride reduction to a diol, which formed an acetonide and hence showed the presence of a β-hydroxy-ester unit in the original alkaloid. Since dehydrogena-tion of dihydro-isositsirikine yielded flavocoryline, a tetracyclic structure very similar to that of sitsirikine could be postulated for isositsirikine. Part II is concerned with the chemistry of cleavamine, a scission product, of the Vinca alkaloid catharanthine. Treatment of catharanthine with aqueous acid in the presence of a reducing agent, led to the isolation of descar-bomethoxycatharanthine, cleavamine and two epimeric dihydro-cleavamines. A tentative mechanism for the reaction is proposed, which can account for the formation of these compounds. Reduction of catharanthine in glacial acetic acid provided carbomethoxy-dihydrocleavamine. Mercuric acetate oxidised this compound to a mixture of two immonium ions, both of which underwent transannular cyclisations. One of the ions gave the known Iboga alkaloids coronaridine and dihydrocathafanthine, whereas the other afforded pseudo-vincadifformine - a synthetic analogue of the known Vinca alkaloid vincadifformine. The structure of pseudo-vincadifformine was determined by conversion into compounds which had U.V., I.R., N.M.R. and mass spectra completely analogous to the corresponding derivatives of vincadifformine. Similar transannular cyclisations to the above are postulated in the scheme advanced by Wenkert for the biogenesis of Iboga and Aspidosperma alkaloids, and the significance of our results with regard to this theory is duscussed. The formation of coronaridine and dihydrocatharanthine in the reaction constituted partial syntheses of these alkaloids, and the potential use of transannular cyclisations in laboratory syntheses of Iboga and Aspidosperma alkaloids is also considered. / Science, Faculty of / Chemistry, Department of / Graduate

The kinetics and mechanisms of macromclecular absorption from the airways of the rat lung were studied in vivo and in vitro, following identical solute administration methods. The isolated perfused rat lung (IPRL) was used as an in vitro model, and the disposition of 7.4 and 4.3 kDa fluorophore-labeled polyhydroxyethylaspartamide (F-PHEA) and other small and macromolecular reference solutes was investigated across doses and in the presence of a variety of biochemical inhibitors. Absorption profiles of F-PHEA, and the solute's lung distribution at different times after administration, were statistically identical in vivo and in vitro, showing that the IPRL possessed a viable mucociliary escalator and that macromolecular solute absorption rates from the IPRL were predictive of those in vivo. A kinetic model of the IPRL incorporating mucociliary clearance alongside active and passive absorption was developed and validated. This model was employed successfully to analyze each solute's absorption components from the rat lung following simultaneous, aeross-dose, nonlinear regression analysis of airway-to-perfusate absorption data. 7.4 and 4.3 kDa F-PHEA absorption from the pulmonary lung compartment occurred actively via the polyaspartamide transporter with values for Vmax,P and Km,p of 4.37/3.60 µg/min and 56.6/76.8 µg, respectively. In contrast, the magnitude of F-PHEA's passive absorption component, ka,p, was inversely related to its molecular weight, consistent with the absorption of a small proportion of each solute dose passing by restricted diffusive transport through tight junctions in the pulmonary epithelium. The active component of 7.4 kDa F-PHEA absorption, which enhanced airway-to-perfusate transfer at low doses, was significantly inhibited in the IPRL at lowered temperature (25 °C; 68.4 %) and in the presence of 1.0 mM 2,4-dinitrophenol (53.3 %), 100 µM ouabain (75.8 %), 30.0 µM monensin (66.0 %) and 30.0 µM noeodazole (68.4 %), This suggested that polyaspartamide-transporter was dependent on ATP-derived energy, and probably employed an intracellular vesicular transcytotic mechanism. The airway-to-perfusate transfer of 376 Da fluorescein and 4.4 kDa fluorophore-labeled dextran had no active (dose-dependent) absorption component. However, each of these solutes showed values for solute's molecular weight-dependent passive absorption and solute-independent mucociliary clearance, when compared to those for F-PHEA.

Lipid-based formulations (LBFs) can be an effective formulation strategy to improve the bioavailability of lipophilic drugs. However, conventional single-compartment in vitro lipolysis assays often underestimate LBF performance in vivodue to the absence of absorption sink. Recently, a two-compartment setup separated by an absorptive membrane provided good in vivo in vitro relationship (IVIVR). The goal of this study was therefore to investigate the use of the artificial membrane “LiDo” in two-compartment assays with regards to digestive enzymes, donor volume and different pH-control methods. The in vivo relevance of the assay was investigated using a single LBF and carvedilol, varying drug-to-formulation ratio and physical state of carvedilol. These formulations were already examined in vivo in a previous study. Digestion was performed using three different enzymes: porcine pancreatin, porcine lipase and Novozyme 435. Due to the incompatibility of pH electrodes with LiDo membrane, high strength lipolysis buffer was tested as alternative to the normal lipolysis buffer. The latter cannot counteract pH decreases caused by lipid digestion and requires dynamic titration.  In vitro assays were conducted in full-size as well as small-size setup. The barrier integrity was evaluated using Lucifer Yellow as a membrane marker. It was found that use of porcine pancreatin best reflected in vivo drug plasma exposure. In contrast, no relationship was observed between in vitro data obtained from lipolysis assays with lipase and Novozymes 435 and in vivo data. Results from assays with lipase may not reliably compare to assays with Novozyme 435 where the latter showed tendency to aggregate in low donor volume, resulting in poor lipid digestion. The outcomes from assays performed in the small-scale setup did not produce good IVIVR either. This outcome could be caused by insufficient agitation in the donor compartment, leading to poor dispersion of LBFs. However, “LiDo'' membrane retained its integrity during lipolysis by all three enzymes. Hence, we can demonstrate further evidence on the utility of LiDo membrane for in vitro lipolysis-permeation.

No description available.

abstract: Single drop impact of liquid on a static powder bed was studied to investigate the granule formation mechanism, droplet penetration time, the characterization of granules (morphology, surface structure and internal structure), as well as the formation regime map. Water was used as the liquid and two pharmaceutical powders, microcrystalline cellulose (MCC) and acetaminophen (APAP), were mixed to make heterogeneous powder beds. The complete drop impact and penetration was recorded by a high-speed camera. Two granule formation mechanisms identified previously occurred: Spreading and Tunneling. Spreading occurred for mixtures of large particle sizes, while Tunneling started to occur when the particle sizes of the mixtures decreased. With an increase of APAP concentration, the overall drop penetration time increased, which was in good agreement with previous literature. The granule morphology, surface structure, and internal structure were characterized by a prism method with image analysis, scanning electron microscope, and X-ray microtomography, respectively. The Spreading mechanism produced flat disks with porous internal structures, while the Tunneling mechanism produced round granules with dense internal structures. Granules that were formed via a hybrid of the mechanisms, Spreading/Tunneling, were hybrid granules, with some dense areas and some porous areas. The results of the granule content uniformity from UV-vis spectrometry revealed that with the increase of APAP proportion, the overall uniformity was compromised for mixtures with fine ingredients, while the content was much more uniform for coarse mixtures. It is believed that the mean particle size of the powder bed is the predominant factor in influencing the formation mechanism, drop penetration time, and granule properties, while the content uniformity is affected by both the particle sizes and the mixture hydrophobicity. / Dissertation/Thesis / Doctoral Dissertation Materials Science and Engineering 2020

Bakgrund: Akut koronart syndrom (AKS) är samlingsbegrepp för instabil angina, icke SThöjningsinfarkt (NSTEMI) och ST-höjningsinfarkt. AKS är en vanlig folksjukdom hos äldre och ungefär hälften av alla över 65 år har kranskärlssjukdom. Kranskärlssjukdom förorsakar cirka 30% av alla dödsfall och är den ledande dödsorsaken globalt. Huvudorsaken till AKS är ateromatös plack som rupturerar och resulterar en ocklusion av kärlen. Perkutan koronarintervention (PCI) utförs som en terapeutisk procedur för att öppna kranskärlen. Efter PCI med stent behövs dubbel trombocythämning under en begränsad tid (1 månad till 1 år) för att motverka reocklusion, därefter behandlas patienter enbart med acetylsalicylsyra (ASA). ASA är det klassiska trombocythämmande läkemedlet och utnyttjas i stort sätt inom hjärt-och kärlsjukdomar. Syfte: Att undersöka nytta-risk balansen med långtidsbehandling av ASA efter AKS jämfört med avbrytande av behandling efter ett år och om tillägg av PPI kan minska blödningsrisken som ASA medför. Metod: En systematisk litteratursökning gjordes i databaserna Pubmed och CINAHL år 2019 respektive 2020. Relevanta studietyper var metaanalyser, kohort, fallkontrollstudier och observationsstudier. Studiernas relevans och kvalitet granskades med hjälp av SBU:s granskningsmallar. Resultat: Nio studier inkluderades, där studieperioden var mellan 6-48 månader. Kvaliteten på dem inkluderade studierna bedömdes vara medelhög. Det framkom att ASA minskar successivt risken för reinfarkt och kardiovaskulär död med en RR på 0,80 i sekundärprevention. Blödningsrisken som ASA medför är högre hos äldre patienter men genom tillägg av protonpumpshämmare kan detta motverkas. Det framkom även att avbrott med ASA behandling ökar risken för reinfarkt och kardiovaskulär mortalitet med >30%. Slutsats: En livslång ASA behandling är viktigt för äldre patienter som upplevt AKS och avbrott av behandlingen ökar risken för reinfarkt och kardiovaskulär mortalitet. Detta påstående framkom 2 av dem inluderade artiklarna med hög respektiv medelhög kvalite. Ett avbrott av ASA behandlingen bör inte därför vara aktuellt för äldre. ASA:s effekt är viktigt och önskvärd efter AKS hos äldre, den sammanlagda nytta-riskbalansen är positiv och det vetenskapliga underlaget för detta påstående är måttligt starkt. Blödningsrisken kan minskas genom att kombinera PPI med ASA, dock behövs fler studier i större population för att stödja detta påstående.