Natural products from marine invertebrates of Port Phillip Bay
Creators: name: Lever, James
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 340502
subject: Natural products and bioactive compounds

description: This thesis describes the investigation of natural products isolated from marine invertebrates sampled from the Port Phillip Bay region of Victoria, Australia. This includes the isolation of an undescribed natural product as well as the isolation of seventeen previously reported natural products from one species of red algae and one marine sponge. This thesis also describes a novel method of targeted isolation along with the application of network science to help understand chemotaxonomy and chemotype drug potential.

Chapter 1 introduces natural products chemistry and a breakdown of some of the isolation approaches used for obtaining or dereplicating natural products in the current era as well as historically. This includes a brief discussion of the relatively recent incorporation of in silico tools into the field of natural products chemistry.

Chapter 2 details methodology and experimental information for all instruments, processes, and compound isolation presented within this thesis. This includes instrument settings, solvent details, reaction procedures and biological assays.

Marine macroalgae occurring in the southeastern region of Victoria, Australia, consisting of Port Phillip Bay and the heads entering the bay, is the focus of chapter 3. This area is home to approximately 200 different species of macroalgae, representing the three major phyla of the green algae (Chlorophyta), brown algae (Ochrophyta) and the red algae (Rhodophyta), respectively. Over almost 50 years, the species of macroalgae associated and occurring within this area have resulted in the identification of many different types of secondary metabolites including terpenoids, sterols/steroids, phenolic acids, phenols, lipids/polyenes, pheromones, xanthophylls and phloroglucinols. Many of these compound classes and their associated bioactivities from marine macroalgae found within this region are reviewed.

The isolation and the structure determination of a new bromophenolic compound, polysiphonol (4.10), as well as five previously reported compounds, (4.4-4.8), from the red alga Polysiphonia decipiens is reported in chapter 4. In addition, the absolute configuration of the natural product rhodomelol (4.8) could be unequivocally confirmed for the first time, and on biosynthetic grounds, the absolute configuration of polysiphonol (4.10) was tentatively suggested. Compounds 4.4-4.8 were evaluated for their antibacterial activity against both Gram-positive and Gram-negative bacteria, but none of the compounds showed any appreciable activity.

Chapter 5 provides a review of all isolated natural products reported for sponges within the order Verongiida (1960 to May 2020) and includes a comprehensive compilation of their geographic and physico-chemical parameters. Physico-chemical parameters were used in this study to infer pharmacokinetic properties as well as the potential pharmaceutical potential of NPs from this order of marine sponge. In addition, a network analysis for the NPs produced by the Verongiida sponges was applied to systematically explore the chemical space relationships between taxonomy, secondary metabolite and drug score variables, allowing for the identification of differences and correlations within a dataset. The use of scaffold networks as well as bipartite relationship networks provided a platform to explore chemical diversity as well as the use of chemical similarity networks to link pharmacokinetic properties with structural similarity. This study paves the way for future applications of network analysis procedures in the field of natural products for any order or family.

Many targeted natural products isolation approaches rely on the use of pre-existing bioactivity information to inform the strategy used for the isolation of new bioactive compounds. Bioactivity information can be available either in the form of prior assay data or via Structure Activity Relationship (SAR) information which can indicate a potential chemotype that exhibits a desired bioactivity. The work described in chapter 6 utilizes a unique method of targeted isolation using structure-based virtual screening to identify potential antibacterial compounds active against MRSA within the marine sponge order Verongiida. This is coupled with molecular networking-guided, targeted isolation to provide a novel drug discovery procedure. A total of 12 previously reported bromotyrosine-derived alkaloids were isolated from the marine sponge species Pseudoceratina durissima, and the compound, (+)-aeroplysinin-1 (6.1) displayed activity against the MRSA pathogen (MIC: &lt;32 μg/mL). The compounds (6.1-6.3, 6.6 and 6.9) were assessed for their central nervous system (CNS) interaction and behavioural toxicity to zebrafish (Danio rerio) larvae, whereby several of the compounds were shown to induce significant hyperactivity. Anthelmintic activity against the parasitic nematode Haemonchus contortus was also evaluated (6.2-6.4, 6.6-6.8).