West, Lyndon

Natural products play a historical role in the discovery of medicine but present unique challenges for chemical isolation, identification and production. In this work we describe the identification of twenty novel diterpenoids. These were isolated by use of chromatography, and the structures determined by spectroscopic methods, primarily 1D and 2D NMR. Six of these possess unprecedented diterpenoid skeletons and two of them show significant growth inhibitory effects on cancer cell lines in vitro (GI50 < 10 μM). The biomimetic semisynthesis of diterpendoids and analogues is also presented.
Access to the bielschowskyane carbon skeleton by dearomatization of a furanocembranoid precursor is described. Highlights include a stereoselective alkene epoxidation, a novel kinetic furan dearomatization method, and an efficient [2+2] photochemical cycloaddition. The role of conformational steering was studied spectroscopically using VT 1H-NMR and NOESY as well as quantum chemical calculations at the DFT level of theory. We also disclose a biomimetic synthesis of providencin using a photochemical Norrish-Yang cyclization. This provided the absolute configuration by chemical correlation with the precursor bipinnatin E, the latter determined by x-ray diffraction. An unexpected, regioisomeric byproduct was observed and a possible mechanism is proposed. A biomimetic synthesis of the diterpene alkaloid aceropterine is also described, using an epoxidation-rearrangement cascade. This work led to a revised structure of aceropterine, formulated by spectroscopic methods. Finally, the isolation and structure elucidation of a novel, cyclic lipopeptide from Pseudomonas sp. is described. The compound was obtained using a unique antibiotic crowd sourcing approach and the structure determined by spectroscopic methods and advanced Marfey’s analysis.

Cacospongia cf. linteiformis is a marine sponge collected from Bahamas possessing
various bioactive compounds. Two pairs of diastereomers spongianolides E&F were isolated for
the first time through function group modification acetylation, and their relative configurations
were determined based on Nuclear Overhauser Effect Spectroscopy NOESY. The mixture of
isomers of spongianolides E&F are exhibiting inhibition against Schnurri-3. Bioassays will be
repeated to unveil the assignment of the bioactivities for the four isomers.

While natural products have served as a prolific
source of unique chemistry, supply remains a significant
obstacle for drug discovery. The overall goal
of this project is to determine whether isolation and
semi-synthesis can provide adequate quantities for
biological evaluation. Erythropodium caribaeorum is
an abundant gorgonian in the Caribbean that produces
two unique marine diterpenoids, erythrolides
A and B, which have been shown to undergo photochemical
transformations to yield more complex
chemistry. In this project, erythrolides A and B will be
isolated from E. caribaeorum collected off the coast
of Boca Raton, Florida. These compounds will be
exposed to ultraviolet light and analyzed to identify
any chemical changes. New compounds will then
be subjected to biological screening for cytotoxicity
against human cancer cell lines. This project will
not only identify new bioactive compounds but also
provide a novel route for the large-scale production
of medically relevant marine natural products.

The aim of this dissertation was to elaborate the exploration of biologically active secondary metabolites from the marine sponge Cacospongia cf. linteiformis collected from the Bahamas and the soft coral Briareum asbestinum collected from two different sites in Florida State, Boca Raton and Dry Tortugas.
In chapter one, a review on previous chemical and biological studies of the marine sponge C. cf. linteiformis and soft coral B. asbestinum is provided. Particular attention is given to spongianolides and briarellins, two important classes of compounds isolated from C. cf. linteiformis and B. asbestinum, respectively, and their structural features and diverse bioactivities.
In chapter two, the isolation and relative configuration determination of four epimeric sesterterpenoids, spongianolides E & F (18c, 18d, 19c, 19d) from C. cf. linteiformis collected from the Bahamas are discussed. Thanks to chemical modification (acetylation), diastereomeric 18c&18d and 19c&19d, respectively, were able to be isolated using chromatographic techniques for the first time, and then the relative configurations of 18c, 18d, 19c, 19d were determined based on NOESY NMR experiments. The bioactivity of mixture of compounds 18c, 18d, 19c, 19d were tested and it exhibited inhibition against Schnurri-3 (a regulator of postnatal bone mass).
In chapter three, the isolation and structural elucidation of four new compounds, florellins A-D (49-52), from B. asbestinum collected off the coast of Boca Raton, FL are discussed. The molecular structures of these compounds were established by spectroscopic analysis. Compounds 49-52 are the first briarellins containing an acyl group at C-13, while 49 and 50 are the first briarellins possessing acylation at C-15. Florellins A–C (49-51) were screened and found cytotoxic against three human cell lines, BT474, WM266−4 and HEK293.
In chapter four, the isolation and structural elucidation of four new compounds, florellins E-H (57-60), from B. asbestinum collected in Dry Tortugas, FL are discussed. The molecular structures of these compounds were established by spectroscopic analysis. Florellins F (58) and H (60) were screened against three human cell lines, BT474, WM266−4 and HEK293, but no cytotoxicity was exhibited.
In chapter five, all the experimental procedures are described, including analytical instruments, animal materials, extraction and isolation processes, spectroscopic data and protocols of bioassays.

The projects described in this dissertation are focused on compounds derived
from marine organisms collected from the western Atlantic marine environment.
Chapter 1 provides an introduction to the study of natural products chemistry,
marine natural products, and overview of the research undertaken from natural product
chemists.
Chapter 2 describes the isolation and structure elucidation of a series of rare
diterpenoids from the gorgonian Briareum asbestinum, together with their conformational
analysis and biosynthetic interconversions. These rare diterpenes from Briareum
asbestinum are linked by an unusual transannular oxa-6π electrocyclization which is
described in detail and this work demonstates the biomimetic hemisynthesis of
briareolate esters L (19) to B (22) achieved via an intermediary, briareolate ester G (2),
through a controlled set of photoinduced isomerizations and a unique photochromic
transannular oxa-6π electrocyclization. This work focuses largely on the mechanistic understanding of the photochemical production of these briarane diterpenoids and
illustrates a unique UVA/UVC, photochromic switch which induces a transannular oxa-
6π electrocyclization.
Chapter 3 describes the assay-guided isolation of marine antioxidants. This
chapter focuses on the screening of marine organism extracts using the Ferric Reducing
Antioxidant Power (FRAP) assay for antioxidant activity guided isolation of marine
natural products. The chapter concludes with the activity guided isolation and structural
elucidation of 1-O-palmitoyl-2-O-myristoyl-3-O-(6-sulfo-α-D-quinovopyranosyl)-
glycerol (40) to show direct antioxidant potential through FRAP analysis.
Chapter 4 describes the isolation, structural elucidation and pharmacological
evaluation of the novel secondary metabolites iso-PsA(45), Iso-PsC (46), iso-PsD (47) as
well as known Pseudopterosins A(41), B(42), C(43), D(44), K(48), K2’OAc(49),
K2’OAc(50). These secondary metabolites were evaluated for both cytotoxicity. The
chapter concludes with the screening of these compounds as αβ-amyloid fibril modulators
utilizing atomic force microcopy (AFM).

The aim of this dissertation was to explore structurally unique secondary
metabolites from herb medicinal plants Cornus controversa and Delphinium
chrysotrichum. The introduction in the first chapter provides a detailed review about the research progress of chemical constitutents of the genus Cornus. In addition, its pharmacological activities were also summarized in this chapter to provide a framework for understanding the roles of medicinal herbs belong to genus Cornus as anti-diabetes therapeutics and to deliver useful information for further research.
In chapter two, seven new compounds, including one iridoid glucoside, cornoside
A (59), five iridoid aglycones, cornolactones A – E (60 – 64) and one indenone
glucoside, cornoside B (65), together with 10 known compounds have been isolated from
the leaves of Cornus controversa. The structures of these compounds were established by
interpretation of spectroscopic data. Cornolactone A (61) is the first natural cis-fused tricyclic dilactone iridoid containing both a five- and six-membered lactone
ring. Cornoside B (65) is the first alkaloid isolated from the genus Cornus bearing an
indole-3-lactic acid-11--D-glucopyranoside skeleton.
In chapter three, we described the structure elucidation of three new diterpenoid
alkaloids delphatisine D (77), chrysotrichumines A (78) and B (79), as well as 11 known
compounds from the whole plants of Delphinium chrysotrichum. Delphatisine D (77) is a
rare atisine-type alkaloid from genus Delphinium and is the C-15 epimer of spiramine C
which bears an internal carbinolamine ether linkage (NCOC) between C-7 and C-20. Chrysotrichumine A (78) is a rare natural C19-diterpenoid alkaloid possessing a nitrone
group between C-17 and C-19. In addition, their cytotoxic activity against human breast
cancer cell lines of MCF-7 and MDA-MB-231 were also reported.
In chapter four, the detailed extraction and isolation procedures of the new
compounds, cornosides A and B, cornolactones A – E, delphatisine D, chrysotrichumine
A and B, as well as of all the known compounds were described. In addition, the
experimental procedures for the determination of PPARγ and LXR agonistic activities
and the MTT cytotoxicity assay were listed in this chapter.