Graduation date: 2001

Recent developments in NMR hardware have extended the reach of natural products chemists to structure elucidation of compounds isolated on a nanomolar scale. In parallel with advances in hardware new NMR techniques for structure elucidation have evolved, e.g. quantitative NOEs, residual dipolar couplings (RDCs)and diffusion-ordered spectroscopy (DOSY). The application of recent NMR techniques was utilized in the screening and structural assignment of natural products isolated from a 2004 collection of South African tunicates. Assignment of the planar structures of mandelalides A-D from a new Lissoclinum sp. was feasible only after data acquisition on a 700 MHz magnet equipped with 5 mm ����C cryogenic probe. While relative configuration of the polyketide mandelalides was established after extensive J-coupling and NOE analysis, quantitative ROESY and RDC measurements were also explored before the absolute configuration was accomplished by chemical degradation and comparison with standards. The application of DOSY, a greatly under-appreciated technique in natural products research, led to the identification of new rubrolide analogues, compounds with moderate antibacterial properties from the new species Synoicum globosum. Finally, relative and absolute configuration of new and known unstable amino alcohols from two Pseudodistoma species was based on J-coupling analysis and application of the Mosher method. / Graduation date: 2013

Graduation date: 1997

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

This thesis is an account of investigation on the natural products deriving from various marine algae and has resulted in the discovery of eleven novel bioactive metabolites. Isolation and characterization of these new molecules were carried out using different chromatographic techniques and by analyses of different spectroscopic data, respectively. Using bioassay guided fractionation (brine shrimp toxicity assay), I isolated and identified five new, biologically active compounds [2β,3α-epitaondiol, flabellinol, flabellinone, stypoaldehyde and stypohydroperoxide], together with five known compounds [2-geranylgeranyl-6-methyl-1, 4-benzoquinone, (-) epistypodiol, (-) stypoldione, fucoxanthin and iditol] from the marine brown alga Stypopodium flabelliforme, collected from Papua New Guinea. All of the new compounds were found to have cytotoxic activity (EC₅₀ ranges from 0.8-10 μg/ml) in human lung cancer (NCI-H460). 2β,3α-epitaondiol and flabellinol exhibited strong sodium channel blocking activity (EC₅₀=0.3 and 0.9 μg/ml, respectively). As a result of efforts to identify bioactive agents from marine algae, I have isolated and identified one new halogenated monoterpene [(-)-(5E,7Z)-3,4,8- trichloro-7-dichloromethyl-3-methyl-1,5,7-octatriene] in addition to another three known halogenated monoterpene compounds from the red alga Plocamium cartilagineum collected from the eastern coast of South Africa. [(-)-(5E,7Z)-3,4,8- trichloro-7-dichloromethyl-3-methyl-1,5,7-octatriene] was found to be active as a cytotoxic agent in human lung cancer (NCI-H460) and mouse neuro-2a cell lines (EC₅₀ 4 μg/ml). As part of continued search for bioactive secondary metabolites from marine sources using a bioassay guided fractionation approach (anti-trypanosome activity), I examined the organic extract of a Papua New Guinean collection of the green alga Udotea orientalis growing on a coral wall and collected in September 1998. Successive HPLC separations resulted in the isolation of three new compounds; (+) curcuepoxide A, (+) curcuepoxide B and (+)-l0α-hydroxycurcudiol. In addition I isolated four known compounds; (+)-10β- hydroxycurcudiol, (+) curcuphenol, (+) curcudiol and (+) curcudiol-10-one. A bioassay guided investigation approach (anti-Sirt2) of a Lyngbya majuscula collection from Key West Florida, led to the discovery of two novel bioactive natural products [(+)-malyngamide X and one cyclic depsipeptide, (+)-floridamide]. The new cyclic depsipeptide, (+)-floridamide contains four amino acids units beside the unique unit, 2,2-dimethyl-3-hydroxyoctanoic acid (Dhoaa). / Graduation date: 2004

The antioxidant and redox properties of L-ascorbic acid are closely associated with the electron rich 2, 3-enediol moiety of the molecule and therefore selective functionalization of the 2- and 3-OH groups is essential for the detailed structure-activity studies. Reactions of 5- and 6-OH protected ascorbic acid with electrophilic reagents exclusively produce the corresponding 3-O-alkylated products under mild basic conditions due to the high nucleophilicity of the C-3-OH. Based on the density functional theory (B3LYP) electron density calculations, a novel and general method was devised for the direct alkylation of the 2-OH group of ascorbic acid with complete regio- and chemo-selectivity. A complete spectroscopic analysis of two complementary series of 2- O -acetyl-3- O -alkyl and 2- O -alkyl-3- O -acetyl ascorbic acid derivatives was carried out to define their spectroscopic characteristics and to resolve common inconsistencies in the literature. The asymmetric approach to the synthesis of natural products or other biologically active compounds is impeded by low abundance of natural sources as well as a limited number of efficient synthetic methods. Nevertheless, carbohydrate-based systems such as the aldono-1,4-lactones (also known as aldono-γ-lactones) which generate a host of chiral compounds have been particularly rewarding in this respect. This study shows a practical approach using 5,6- O -isopropylidene-L-ascorbic acid (ketal of L-ascorbic acid) as a single common starting material for facile asymmetric synthesis of protected, optically pure and functionalized aldono-1,4-lactones derivatives, valuable in the synthesis of derivatives of various pharmacologically active agents for structure-activity studies. The practicality of this new approach is demonstrated by the convenient synthesis of a series of thermal Claisen-rearranged products of 5,6- O -isopropylidene-3- O -allyl-L-ascorbic acid and 5,6- O -isopropylidene-2- O -allyl-L-ascorbic acid as the corresponding 5,6- O -isopropylidene-2-allyl-3-keto-L-galactono-γ-lactone and 5,6- O -isopropylidene-3-allyl-2-keto-L-galactono-γ-lactone respectively. The synthetic routes are economical, efficient, diastereospecific, and proceed in high yields. / "August 2005." / Thesis (Ph.D.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry.

Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. We demonstrated that curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of survivin, VEGF and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on downregulation of Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. Curcumin decreases expression of Sp1, Sp3 and Sp4 in blader cancer cells indicating that the cancer chemotherapeutic activity of curcumin is due, in part, to decreased expression of Sp transcription factors and Sp-dependent genes. Betulinic acid (BA) and curcumin are phytochemical anticancer agents, and we hypothesized that both compounds decrease EGFR expression in bladder cancer through downregulation of specificity protein (Sp) transcription factors. BA and curcumin decreased expression of EGFR, Sp1, Sp3, Sp4 and Sp-dependent proteins in 253JB-V and KU7 cells; EGFR was also decreased in cells transfected with a cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3 and Sp4 showing that EGFR is an Sp-regulated gene. Methyl 2-cyano-3,11-dioxo-18?-olean-1,12- dien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid which inhibits proliferation of KU7 and 253JB-V bladder cancer cells. CDODA-Me also decreased expression of specificity protein-1 (Sp1), Sp3 and Sp4 transcription factors. Similar results were observed for a structurally-related triterpenoid, methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me), which is currently in clinical trials for treatment of leukemia. Celastrol, a naturally occurring triterpenoid acid from an ivy-like vine exhibits anticancer activity against bladder cancer cells. Celastrol decreased cell proliferation, induced apoptosis and decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and several Sp-dependent genes like Fibroblast growth factor receptor 3 (FGFR3). In vivo studies using KU7 cells as xenografts showed that celastrol represents novel class of anticancer drugs that acts, in part, through targeting downregulation of Sp transcription factors.

Coibamide A is a methyl-stabilized cyclic depsipeptide with a lariat side chain that was isolated from a marine cyanobacterium as part of an International Cooperative Biodiversity Groups program based in Panama. Previous testing of this potent and selective growth-inhibitory agent in the National Cancer Institute (NCI) in vitro 60 human cell line panel revealed a "COMPARE-negative" profile indicative of a unique mechanism of action. Presented herein is a collection of studies characterizing the mechanism of action of coibamide A and cataloguing the cytotoxicities of putative coibamide A and related structures from efforts at its total synthesis. We report that coibamide A induces apoptotic and non-apoptotic cell death in human U87-MG and NCI-SF-295 glioblastoma cells, respectively, which can occur independently of a rapid and sustained mTOR-independent autophagic response. Loss of cell viability from coibamide A exposure was concentration-dependent and time-sensitive, characterized by extensive cytoplasmic vacuolization and an absence of apoptotic morphology and DNA fragmentation prior to cell rounding and detachment from the substratum. Coibamide A also induces a cytostatic effect mediated by a G1 phase specific cell cycle arrest and inhibits glioma cell invasion but not migration. Lastly, structure activity relationships suggest that linearization, loss of N-methylation and disjoining of the cyclic and side chain structures of coibamide A are not well-tolerated modifications to retain activity. / Graduation date: 2013 / Access restricted to the OSU Community at author's request from Jan. 8, 2013 - Jan. 8, 2014

The pyrrole-imidazole alkaloid family of natural products illustrates the diversity of topographically unique molecules with potent biological activities that can be found in the marine environment. Thus, great interest for this class of compounds has developed leading to new synthetic methodologies and tactics to build these complex secondary metabolites. The overall objectives of this research project include the total synthesis of the phakellins and phakellstatins. First, we revisited the strategy developed in our group for the total synthesis of (+)-dibromophakellstatin and utilized it for the synthesis of its naturally occurring enantiomer and congeners. Second, we proposed and studied a new and more concise approach to the phakellstatins and phakellins based on a key C-H insertion process developed by Du Bois. Attempts to streamline the first synthesis of (+)-dibromophakellstatin proved to be quite challenging. Shortcomings in the reproducibility of some parts of the original strategy precluded us from completing and making more efficient the synthesis of the natural enantiomer (-)-dibromophakellstatin. Fortuitously, our second generation approach though it presented itself as an efficient route to the phakellins and phakellstatins produced the undesired anti diastereomer of the key guanidine intermediate which precluded our study of the pivotal C-H insertion reaction.

The organic extracts of two marine soft corals Pachyclavularia violacea and Subergorgia suberosa, collected along the coast of Kenting, Taiwan, were found to exhibit significant cytotoxicities toward several cancer cell lines (Table 1). In order to discover bioactive compounds, we have investigated the chemical constituents of these two marine organisms. Investigation on P. violacea has led to the isolation of twenty-five compounds, including twenty-one new compounds, pachyclavulariolide G (1), pachyclavulariolide H (3), pachyclavulariolide I (4), pachyclavulariolides J¡VS (6¡V15), pachyclavulariaenones A¡VG (16¡V22), secopachyclavulariaenone A (23), and four known compounds pachyclavulariolide (2), pachyclavulariolide E (5), pachyclavulariolide A (24) and pachyclavulariolide B (25). Also, we have investigated the chemical constituents of S. suberosa. This study led to the isolation of fifteen compounds, including six new compounds, 2b-acetoxysubergorgic acid (27), subergorgiol (31), suberosols A¡VD (34¡V37), and nine known compounds, subergorgic acid (26), 2b-hydroxysubergorgic acid (28), methyl ester of subergorgic acid (29), 2b-acetoxy methyl ester of subergorgic acid (30), buddledin D (32), buddledin C (33), 5b-pregnan-3,20-dione (38), £G1- 5b-pregnen-3,20-dione (39) and 3a-acetoxy -5b-pregnan-20-one (40). Compounds 39, 40 were isolated from natural sources for the first time. Structures of these compounds were determined on the basis of chemical method and spectroscopic evidences. Cytotoxicities of these compounds against P-388, KB, A-549 and HT-29 cancer cell lines also were described. Compound, 7, 32, 33, 36, 37 have been found to show moderate activity toward the above cancer cell lines.