Graduation Year
2019
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Chemistry
Major Professor
Bill J. Baker, Ph.D.
Committee Member
James W. Leahy, Ph.D.
Committee Member
Dennis E. Kyle, Ph.D.
Committee Member
Theresa Evans-Nguyen, Ph.D.
Keywords
anverenes, dendrillins, membranoids, metabolomics, natural products
Abstract
Chemical ecology is the study of chemical interactions between organisms and their environment mediated by small molecules involved in nonessential physiological functions, known as secondary metabolites. These compounds can be crucial to survival of the organism, and have also provided the field of medicine with some of history’s most influential drugs, referred to in that context as natural products. Antarctica is a dynamic and understudied environment, which affords the opportunity to examine the chemical ecology of unique organisms while simultaneously evaluating their novel chemistry for potential therapeutic properties as natural products.
Plocamium cartilagineum is a red macroalgal species found in the shallow waters of Antarctica known to produce many cytotoxic polyhalogenated monoterpenes thought to serve as feeding deterrents to sympatric algal consumers. Individuals around Palmer Station on Anvers Island can be classified into two distinct genotypes, both shown to produce varying combinations of these chemical defenses linked with site specificity, suggesting each alga is able to tailor its defenses to better suit its unique set of environmental conditions. Metabolomic data linked with genomic analysis from newer and larger field collections during the 2016-2018 field seasons show an even greater diversity of chemical phenotypes than previously found, and that both genotype and depth seem to play a role determining the constituency of the chemical feeding deterrents produced.
In an attempt to further evaluate this diversity, the major components of several of the most common chemogroups at our collection sites were determined using GC/MS and NMR guided fractionation. In the process, a small library of anverene-like (2.22) polyhalogenated monoterpenes was generated, containing several known compounds and four previously undescribed natural products, referred to as anverenes B-E (2.29-2.31, 2.34). This collection of molecules was screened for cytotoxicity towards human cervical cancer cells, and displayed moderate potency, with oregonene A (2.9) and new structure anverene C (2.30) showing near-nanomolar activity.
Another common species which dwells in the Antarctic benthos and is rich defensive terpenoids is the marine sponge Dendrilla membranosa. Numerous prior investigations into the secondary metabolome of this sponge has revealed a range of oxidized diterpenes with high variability between collections, leading us to hypothesize that selective predation pressures related to the presence of habitats dominated by macroalgal canopies could be driving the chemical diversity. Metabolomics studies were carried out using HPLC-ELSD and provide evidence that there are in fact distinct chemical phenotypes produced by sponges dwelling within the different habitats. Statistical analysis shows that levels of 9,11-dihydrogacilin A (3.10) and tetrahydroaplysulphurin-1 (3.14) were significantly correlated with habitat, suggesting that production of these metabolites could be driven by their effectives against specific predators.
Concurrent with this study was the generation of another chemical library containing diterpenoid secondary metabolites and semisynthetic derivatives from D. membranosa with promising bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and MRSA biofilm. In total, 11 natural products and 7 semi-synthetics were isolated or derived from this cold-water poriferan resulting in a collection of 18 compounds, with 5 new or revised semi-synthetic structures in the newly named membranoid series (4.12-4.18), and 3 new natural products designated dendrillins B-D (4.29-4.31) among the compounds tested. Several of the membranoids and dendrillins showed high potency against the leishmaniasis parasite with the new structure membranoid B (4.13) displaying sub-micromolar activity with no observed cytoxicity towards human cells. Among others, newly revised membranoid D (4.15) showed promising low micromolar activity against the liver-stage malaria parasites, while membranolide (3.15) is a promising lead against MRSA biofilm cultures and warrants further investigation.
Scholar Commons Citation
Shilling, Andrew Jason, "The Chemical Ecology and Drug Discovery Potential of the Antarctic Red Alga Plocamium cartilagineum and the Antarctic Sponge Dendrilla membranosa" (2019). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/8684
