Prenylated phenols constitute a prominent class of natural products commonly found in plants and fungi that demonstrate many biological effects. In general, relative to their corresponding non-prenylated parent phenol compound, phenols bearing -prenyl, -geranyl, or - farnesyl substituents tend to show enhanced bioactivities, potentially due improved cell permeation associated with greater lipophilicity. Five prenylated isoflavone natural products: corylifol A, neobavaisoflavone, myrsininone A, isowighteone, and methyl corylifol A are isolated from distinct fungal or plant species and associated with diverse biological profiles. These natural products are of interest due to their demonstrated biomedical potential. Many isoflavones and other prenylated flavonoids exhibit excellent antioxidant and anticancer activity. These isoflavone natural products, along with five related novel compounds are synthesized using regioselective ortho-allylation of phenolic boronic ester mediated by acidic alumina, followed by a Suzuki cross- coupling with a functionalized chromone. / Thesis / Master of Science (MSc)

As part of an International Cooperative Biodiversity Group (ICBG) program and a collaborative research project with the Natural Products Discovery Institute, twenty plant extracts were investigated for their antiproliferative and antimalarial activities. Bioassay guided fractionation of thirteen extracts led to the identification of three new antiproliferative compounds, ethyl leptaulosides A-C (5.1-5.3), six new antiplasmodial compounds, apoplanesiacarpan A and B (2.4-2.5), (±)-rhodomyrtosone F (3.1), (±)-calliviminone C (3.2), 3α-angeloyloxy-15-hydroxylabda-7,13-dien-16,15-olid-18-oic acid (4.1), 3α-angeloyloxy-15-methoxylabda-7,13-dien-16,15-olid-18-oic acid (4.2), and twenty-six known compounds. The structures of these compounds were elucidated by using a combination of 1D (1H and 13C) and 2D NMR spectroscopy, mass spectrometry, UV, IR, CD, optical rotation, and chemical modifications. Compounds 5.1 and 5.2 showed moderate antiproliferative activity against the A2780 human ovarian cancer cell line assay with IC50 values of 3 uM and 10 uM, respectively. Compound 3.1 showed potent antiplasmodial activity with an IC50 value of 100 nM, while compounds 3.2 and 4.1 showed moderate antiplasmodial activity with IC50 values of 4 uM and 10 uM, respectively. The other compounds had IC50 values larger than 20 ug/mL, and were thus either inactive or only weakly active. / Ph. D. / Plant based natural products have a long history of being used for medicinal purposes and have played an important role in the modern drug discovery program, with the best known examples being paclitaxel as an anticancer drug, and quinine and artemisinin as antimalarial drugs. Despite great progress in fighting malarial and cancer, both diseases remain difficult to combat due to emergence of drug resistance in malarial parasites and hardness to treat various types of cancer. Therefore, it is urgent to discover new antimalarial and anticancer agents to treat these deadly diseases. This research focuses on identifying new antimalarial and anticancer agents from plant extracts. Investigation of twenty plant extracts led to the isolation of three new anticancer, six new antimalarial and twenty-six known compounds. The isolation and structure elucidation of these new bioactive compounds will be discussed in this dissertation.

Thesis (M.Sc.)--Victoria University of Wellington, 2008. / Includes bibliographical references.

The enantioselective approach to bonandiol, also known as magydardiendiol, has utilized two novel synthetic methodologies. The first is the diastereoselective cyclopropanation of a homochiral eneketal prepared from (2R,3R)- or (2S,3S)-2,3-butanediol and possessing C₂ symmetry. Simmons-Smith cyclopropanation gave good diastereoselectivity (69-75%) in addition to excellent amounts of monocyclopropanated material obtained (90-96%). The second method utilized is the nickel acetylacetonate catalyzed coupling of dimethylzinc to a sterically hindered cyclic β-keto enolphosphate in 76-92% yield. This approach to the A ring of hyperforin starting from commercially available citral allows for the introduction of all but one isoprenyl appendage.

Small molecules containing a 7-deazapurine moiety are ubiquitous in nature. They comprise a broad range of structurally diverse antibiotics produced by terrestrial and marine microorganisms that possess demonstrated antibiotic and antineoplastic activity. In addition, queuosine, a hypermodified nucleoside located in the wobble position of select tRNAs that is almost universally conserved throughout biology, contains a 7-deazapurine functional group. The since their initial identification over 50 years ago, the chemical transformations underlying the biosynthesis of 7-deazapurines have remained elusive. This work describes the identification of a cluster of co-localized genes in the Streptomyces rimosus chromosome that are responsible for the biosynthesis of the 7-deazapurine containing antibiotics toyocamycin and sangivamycin. Further, the in vitro conversion of GTP to the previously identified queuosine biosynthetic intermediate 7-cyano-7-deazaguanine (preQ₀) is demonstrated using purified, recombinant enzymes. Also included herein is a kinetic, spectroscopic, and mechanistic characterization of QueE, an enzyme that catalyzes the third step in the biosynthesis of 7-deazapurines using a radical-mediated rearrangement. A possible mechanism for the reaction catalyzed by QueD, the second step in the deazapurine biosynthetic pathway, is explored based on X-ray crystallographic data of site directed QueD mutants containing bound substrate. Finally, hitherto unrecognized gene clusters that are likely devoted to the biosynthesis of 7-deazapurines other than queuosine are described.

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The use of natural antioxidants to improve the oxidative stability of food lipids has received special attention because of the worldwide trend to avoid the use of synthetic food additives. A wide range of natural sources has been shown to contain antioxidant properties, these include plant extracts, herbs and spices, citrus fruits, oilseeds and legumes. Some antioxidants have been found to be fonned during the heat processing of foods, including the Maillard reaction products that are formed by the reaction of amino acids, peptides and proteins with reducing carbohydrates. A study was undertaken to investigate the antioxidant activity of Maillard reaction products fonned during extrusion of soyabeans. A preliminary oxidation study carried out to identify a suitable substrate revealed that sunflower oil stripped of antioxidants was a suitable substrate with a low induction period of 15 minutes via the Rancimat Method and 4.5 hours via the method of Ross and de Muelenaere. Methyllinoleate was found to be sensitive to oxidation, but not readily available and costly. Storage test of antioxidant stripped sunflower oil under various headspace conditions showed that the substrate stability was best at 4°C under nitrogen or vacuum. Under such conditions the product could be stored for a period of 136 days. Nitrogen was chosen as the most suitable for this exercise as it was not easy to remove all residual air from the samples by vacuum. Furthermore with nitrogen headspace residual 02 could be measured based on Ni02 ratio changes. Hexane solvent was found to be able to remove all lipids from soyabeans. Under the experimental conditions practised it was found that the induction periods for extruded and unextruded soya flour hexane extracted lipids were very similar. Addition of glucose or fructose to the extrusion mixture increased induction period of hexane extracted lipids by 37.5% and 1.5% respectively as measured by the Ross and de Muelenaere method and by 50% and 6.5% respectively as measured by the Rancimat Method. Available lysine of glucose containing extrudate was reduced by 69% while that of the fructose containing extrudate was reduced by 23%. Residual glucose and fructose analysis of extrudates showed that 66% of glucose was utilized in the formation of the Maillard reaction products while only 21% of fructose was utilized during extrusion processing. Comparison of induction periods of soya glucose and soya fructose extrudates to induction period of TBHQ antioxidants (200ppm) in antioxidant stripped sunflower oil gave antioxidant activity of 86ppm and 9ppm for soya glucose extrudates and soya fructose extrudates respectively. The observed antioxidant activity of Maillard reaction products could be utilized with success in different types of processed foods without the need for extensive testing as required for synthetic antioxidants but supplementation of lysine may be required to maintain nutritional balance. / Thesis (M.Sc.)-University of Natal, 1994.