Natural products have been a fundamental source of medicinal scaffolds for decades; with sixty percent of marketed drugs. Many synthetic chemists are focused on synthesizing potent and nontoxic compounds for pharmaceutical targets, however, nature is still proving to be a source of new bioactive compounds. Produced by the host organism for defense, reproduction and communication, secondary metabolites also demonstrate promising bioactivity against human pathogens. Hence, natural product chemists continue their quest for new leads. As a continuation of these efforts, this thesis attempts to explore fungi and sponges for new chemistry, and ultimately, new drug candidates. Antarctica is largely untapped; hence herein two Antarctic sponges were chemically investigated. This resulted in isolation and characterization of two metabolites. Concurrently, chemical investigation of fungus, from Floridian mangrove species, resulted in the isolation of two structurally diverse metabolites. Further, a dereplication process was applied to MPLC fractions, which lead to the identification of known metabolites and mycotoxins. This enabled prioritization of fractions for future studies.

This thesis details my investigations of marine cyanobacterial natural products that resulted in the discovery of eighteen new secondary metabolites. Isolation and characterization of these unique molecules were carried out using different chromatographic techniques and by careful analyses of 1D and 2D NMR data, respectively. Preliminary bioassays of the crude organic extract of the marine cyanobacterium Lyngbya semiplena collected from Papua New Guinea in 1999, showed good activity in the brine shrimp toxicity model at 10 ppm. Guided by this assay, seven new anandamide-like fatty acid amides, semiplenamides A to G, together with four cyclic depsipeptides, wewakpeptins A to D, were identified. Due to the structural resemblance of the novel ethanolamide derivatives (semiplenamide A-G) with anandamide, (N-arachidonoyl-ethanolamine), an endogenous agonist of cannabinoid receptors compounds, semiplenamide A-G were tested on the well characterized proteins of the endocannabinoid system: 1) the "central" cannabinoid CB₁ receptors; 2) the anandamide membrane transporter (AMT), which is responsible for anandamide cellular uptake; and 3) the fatty acid amide hydrolase (FAAH), which catalyses anandamide hydrolysis. Three showed modest potency in displacing radiolabeled anandamide from the cannabinoid receptor (CB₁), and one was a modest inhibitor of the anandamide membrane transporter (AMT). The wewakpeptins were tested for cytotoxicity to NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells. Intriguingly, wewakpeptin A and B were approximately 10-fold more toxic than C and D to these cell lines. Lyngbya majuscula has been recognized as a chemically and biologically rich strain. Five new lyngbyabellin analogs, lyngbyabellins E-I, along with the known compound dolabellin, originally isolated from sea hare Dolabella auricularia, were identified from a 2002 Papua New Guinea collection of the marine cyanobacterium Lyngbya majuscula. The lyngbyabellins were tested for cytotoxicity to NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells and had LC₅₀ values between 0.2 and 4.8 μM. Intriguingly, lyngbyabellin E and H appeared to be more active against the H460 cell line with LC₅₀ values of 0.4 μM and 0.2 μM, respectively, compared to LC₅₀ values of 1.2 and 1.4 μM in the neuro-2a cell line. Lynbyabellin I was the most toxic to neuro-2a cells (LC₅₀ 0.7 μM), whereas lyngbyabellin G, was the least cytotoxic of all compounds to either cell line. On the basis of this limited screening, it appears that lung tumor cell toxicity is enhanced in the cyclic representatives, and overall potency is increased in those containing an elaborated side chain. Additionally, two new cytotoxins, aurilides B and C, which are closely related to aurilide, originally isolated from the sea hare Dolabella auricularia, have been identified from the same extract where the lyngbyabellins E-I were isolated. Aurilides B and C were tested for cytotoxicity to NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells. Interestingly, aurilide B was approximately 4-fold more toxic than C to these cell lines. The LC₅₀ for Aurilide B was 0.01 μM and 0.04 μM for neuro-2a and H460 cells, respectively, and 0.05 μM and 0.13 μM, respectively, for aurilide C. Aurilide B was evaluated in the NCI 60 cell line panel and found to exhibit a high level of growth inhibition in leukemia, renal, and prostate cancer cell lines with a GI₅₀ less than 10 nM. Aurilide B showed net tumor cell killing activity in the NCI's hollow fiber assay, an in vivo model for assessing a chemical's anticancer activity. / Graduation date: 2006

This work can be separated into two parts; the first will encompass chapters one and two, which discuss the use of the Catellani reaction to access different heterocycles. The second part will encompass the remaining chapters and deals with stereoselective reactions of arynes. Chapter one outlines the development of a general and high yielding synthesis of the phenanthridine nucleus via a palladium-catalyzed domino reaction of aryl iodides with N-H or N-trimethylsilyl imines. This strategy was applied in a succinct synthesis of benzo[c]phenanthridine alkaloids nitidine and NK109. Chapter two details the development of a Catellani-type reaction of aryl iodides with 2H-azirines. Conditions were found to selectively provide access to either the indole nucleus or unusual dihydroimidazoles. The yields of the products ranged from moderate to good, however, the success of the reaction is highly dependent on the structure of the 2H-azirine. A mechanism was proposed involving oxidative addition of the azirine to generate an azaalyl intermediate. In Chapter three the foray into the area of aryne chemistry begins. A stereoselective nickel- catalyzed [2+2+2] cycloaddition of 1,6-enynes with aryne intermediates was developed. Attempts were made at the development of an asymmetric variant of the reaction, however, only low enantiomeric excess was observed. Good diastereoselectivity could be obtained when an allylic substituent was present. The yields of the products ranged from moderate to excellent. However, the yields vary greatly and in a number of cases the reactions were unsuccessful. Finally, in chapter four the development of a general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction and it that regioselective hydrogen migration occurs. Furthermore, the electronic nature of the aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggested a concerted asynchronous transition state, resembling a nucleophilic attack on the aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine. In a similar vein, preliminary results demonstrating an intramolecular, formal [2+2] cycloaddition of an aryne with an S, O-ketene acetal to give interesting tricyclic benzocyclobutene products are disclosed.

The development of machine vision algorithms for inspection and machine guidance has traditionally relied on the knowledge and experience of the developers as most of the techniques are based on heuristics and trial and error. This is especially problematic in the area of natural products where variability of the products is the rule rather than the exception. Humans are particularly good in functioning in this arena and in this thesis we look at the development of techniques derived from the functions of the human visual system (HVS). We first identify the significant processes in the HVS and highlight those that we believe are germane to the problems of interest. We then develop computational techniques using these methods and demonstrate their applicability to practical problems. This thesis uses the knowledge that the HVS is considered to consist of three sequential operations (sensing; encoding/transfer; and image interpretation) as a basis for developing a parallel procedure for a machine vision system. We have found that outputs derived from a simulation of the behaviors of receptive fields in the retina and in the higher levels of the brain can generate useful and robust features. Equivalent processes are then developed for machine applications under the guidance of a human operator to identify the areas of interest in the scene for the problem under consideration. Specifically we use the processes for encoding/transfer of data from the retina to develop techniques to enhance color contrasts, and compute color image features that are useful for defect detection and identification in real world images. This is accomplished by a transformation from image space to a characteristic response space that improves the robustness of classification. In this thesis the approach developed is applied to two industrial problems in the quality monitoring of meat and vegetables. The first problem concerns the quality monitoring of breast butterflies and the other the detection of defects on the surface of citrus. The approach is shown to derive algorithms that are robust and can be implemented at high rates of speed. Additionally we also identify a model within which further developments can be conducted as we learn more about the functioning of the HVS.

In recent years, marine natural products in drug development increasingly wide range of applications. Both Taiwan's geographical location and climate are creating a rich marine biodiversity. Hence there is needed to construct a marine natural product database which with Taiwan features. The goal of this study is to establish a Taiwan's marine natural product database, with preliminary collected Formosan soft coral diterpenoids natural products from Taiwan for drug development features. The database included normal physical and chemical properties of compounds and biological activity assay from literature. Key project for the database is to construct three-dimensional structure information for marine natural products. In this study, it was to build and to check the correct three-dimensional structure by use of computer simulation study comparing with nuclear magnetic resonance (NMR) spectroscopy information from literature. The identification of the folding errors in three-dimensional structure of various compound skeleton types by computer was also discussed. And there was also discussed the relationship between potential energy and three-dimensional structure of compounds by compare with computer simulated structure and NMR structure.

We have successfully using the exocyclic double bond of tricarbonyliron triene complexes to undergo (2+1) and (4+2) cycloaddition for the rapid construction of spiro[2.5]octane and spiro[5.5]undecane system. These cycloaddition reactions were chemo-, regio-, and stereoselective. Synthetic studies toward Upenamide, Manzamine A and Manzamine J by using 1-cyano-2,4-cyclohexadiene tricarbonyliron complexes were also discussed.

Calophyllum inophyllum is a medicinal plant that is rich in bioactive natural products. Calophinone¡]29¡^¡Bcaloxanthone I¡]30¡^¡Bbrasilixanthone B¡]31¡^¡Bpyranojacareubin¡]32¡^ and osajaxanthone¡]33¡^are five compounds which were isolated from the bark in this experiment. It is the first time to isolate calophinone¡]29¡^ from a matural source. In order to identify calophinone¡]29¡^, 6-acetylcalophinone¡]34¡^ was prepared via acylation. All structures were determined primarily on the basis of 1D, 2D NMR¡BUV¡BIR and Mass spectral analyses. Besides, biological studies don¡¦t reveal that Calophinone¡]29¡^¡Bcaloxanthone I¡]30¡^¡Bbrasilixanthone B¡]31¡^¡Bpyranojacareubin¡]32¡^¡Bosajaxanthone¡]33¡^and 6-acetylcalophinone¡]34¡^, exhibited in vitro cytotoxicity against human liver carcunoma¡BHuman oral epidermoid carcunoma and Human cervical epidermoid carcunoma. In addition, four new Taxoid derivatives that were 13-O-camphanyl-7-O -nicotinoylbaccatin III¡]34¡^¡B13-O-camphanyl-1-deoxybaccatin VI¡]35¡^¡B13-O-¡]4-chlorobenzoyl¡^-7-O-nicotinoylbaccatin III¡]36¡^and 13-O-benzoyl-7-O -nicotinoylbaccatin III¡]37¡^have been prepared via esterification under sonication starting from 13-deacetyl-7-O-nicotinoylbaccatin III¡]32¡^ and 13-deacetyl-1-deoxybaccatin VI¡]31¡^. All the structures were established primarily on the basis of 1D and 2D NMR techniques including DEPT, COSY, HMBC experiments, as well as comparison with known related compounds. It was deemed quite promising to investigate the structure-activity relationship ( SAR ) for the C - 13 side chain analogues of Taxol with some modification of the baccatin III¡]30¡^ moiety in order to discover more effective anticancer agents with better pharmacological properties. Compounds 34 and 35 showed significant cytotoxicity against prostate cancer cell line¡]PC-3¡^. Under concentration of 10£gM, the cell survival percent was 76% and 65% in case of compounds 34 and 35 compared to 60 % in case of Taxol. According to the structure-activity relationship, nicotinoyl and camphanic acyl group should be the source of activity in compounds 30 and 31. Consequently, it is necessary to introduce nicotinoyl chloride and camphanic acyl chloride groups via chemical reaction to improve the bioactivity.

Thesis (Ph. D.)--University of Alberta, 2009. / Title from pdf file main screen (viewed on Dec. 21, 2009). "A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Chemistry Department, University of Alberta." Includes bibliographical references.

Ischemic stroke is a leading cause of disability and death around the world. Higher concentration of glutamate following ischemic stroke is a factor leading to cell death, including neural stem cell death. Up to now no effective treatments of ischemic stroke are available. Notoginsenoside R1 (Noto R1) is the main component of Panax notoginseng, which is a traditional Chinese medicine for the treatment of cardiovascular disease. Its protective effects on the neural cell were noted recently. The main purpose of this experimental study was to investigate the mechanism of Noto R1 against glutamate neurotoxicity on primary cultured mouse cortical neural stem cells in vitro, and its effects on ischemic stroke on mice brain in vivo. In the in vitro part, primary culture of neural stem cells was prepared from 12.5-day-old C57BL/6N mice embryos cortex. Neural stem cells were confirmed by nestin-staining and differentiation study afterwards. Then neural stem cells were incubated with Noto R1 and glutamate for 24 hours. Cells were fixed for TUNEL staining and caspase-3 staining. Protein was collected for western blot for Bax, Bcl-2, phos-AKT, JNK/SAPK, and phospho-p38 MAPK. Results showed that glutamate has cytotoxicity in a dose-dependent manner on neural stem cells. Noto R1 showed remarkable neuro-protective effects on neural stem cells exposed to excessive glutamate by higher viability. Noto R1 significantly reduced caspase-3 expression and TUNEL-positive cells. Furthermore, Noto R1 increased the protein expression of Bcl-2 and phospho-AKT, and reduced Bax expression. Moreover apoptosis pathway study showed phospho-p38 expression was suppressed in the Noto R1 group. In the in vivo part, Noto R1 was administrated systemically to mice of MCAo followed by reperfusion. Behavior score and viability rate were assessed before sacrifice. TTC staining was performed for evaluating infarct area, volume and edema. H&E staining was applied for histological examination. TUNEL staining, IHC staining of Nestin, AQP4 and GFAP were performed. In the first part of Noto R1 of 40 mg/kg or PBS was injected into venous at the onset of blood vessel occlusion for 2 hours, and then followed by 22 hours of reperfusion. Results were all negative. In the second part, Noto R1 was injected intra-peritoneum for 10 days prior to MCAo which lasted for 1 hour 50 minutes, then reperfusion was allowed for 22 hours. Results showed Noto R1 improved behavior score and viability rate. Meanwhile Noto R1 significantly reduced ischemic area, volume and edema percentage. Moreover TUNEL-positive cells in the affected cortex were significantly decreased. Nestin-positive cell in the striatum were significantly increased in the Noto R1 group, and immunoactivity of AQP4 and GFAP was apparently decrease with Noto R1 treatment. In conclusion, this study showed that Noto R1 protected cultured neural stem cells against glutamate neurotoxicity in vitro via p38 MAPK pathway by inhibiting Bax protein expression and enhancing protein expression of Bcl-2 and phospho-AKT. Moreover, it also demonstrated significant preventive effects against ischemic stroke with mice model in vivo. In a word Noto R1 presents a highly potential candidate preventing ischemic stroke clinically in the future. / published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

The fungal metabolites vinaxanthone and xanthofulvin possess the remarkable ability to restore motor function in animal models of complete spinal cord transection making them the most promising small molecules for the development of spinal cord injury (SCI) therapeutics. A concise nine-step total synthesis of vinaxanthone was accomplished utilizing a biomimetic dimerization of the putative precursor 5,6-dehydropolivione and the first reported synthesis of xanthofulvin was achieved in 15-steps highlighted by an unprecedented enaminone O-to-C carboxyl transfer to forge key carbon-carbon bonds. Both natural products were also identified as positive allosteric modulators of the G-protein coupled receptor (GPCR), GPR91, thus elucidating their modes of action accounting for their regenerative capabilities. Furthermore, a unique ynone coupling reaction was developed in order to access various vinaxanthone analogs for structure activity relationship (SAR) studies. This resulted in the preparation of a small molecule library of 25 vinaxanthone analogs that demonstrated pronounced neuronal regeneration within laser axotomy assays performed in vivo on C. elegans. The plant derived natural product eupalinilide E has been found to promote the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs) which have the potential to improve the success of medical procedures such as bone marrow transplants. In light of its promising applications, unknown mechanism of action, and scarcity in nature the total synthesis of eupalinilide E was undertaken. Efforts culminated in the first enantioselective total synthesis of the natural product in 20-steps, which showcases a Favorskii rearrangement, borylative enyne cyclization, aldehyde-ene ring closure, and a dual allylic oxidation. / text