Date of Award

2022

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Skylar Carlson

First Committee Member

Jerry Tsai

Second Committee Member

Andreas Franz

Abstract

Natural products are small organic compounds synthesized by living organisms including plants, animals, and microbes. These fall into one of two categories, primary metabolites are required for survival, but secondary metabolites usually play a more accessory role. Extracts from organisms have proven to be useful to humans throughout history. Prior to evidence-based western medicine practices, natural products were the only source of medicine and remain as a treatment source for underdeveloped nations. Today, natural products have either been approved by or have served as the template for many FDA approved drugs. Based on a survey of all FDA approved drugs between 1981 and 2019, 4% were pure natural products, 19% were natural product derivatives, and 3% were synthetic drugs with a natural product inspired pharmacophore.

These compounds can also play an important role in providing survival advantage through protection from predation and competition, or by mediating interaction between individuals. Chemical ecology is the study of the role natural products play in the environment. Throughout my thesis, I aimed to understand the ecological role of the compounds I isolated. My two main projects explored anticancer compounds from marine cyanobacteria that were detected in the surrounding seawater and the role of root exudates in kin-recognition and chemical communication.

Marine cyanobacteria are a prolific source of biologically active natural products, many of which demonstrate potent pharmacological activities. The serine protease, elastase, has been shown to play a role in tumor progression leading to metastasis. The inhibition of which has been previously linked to reduced cancer cell motility. Ahp (3-amino-6-hydroxy-2-piperidone) containing cyclic depsipeptides are potent serine protease inhibitors. The Ahp unit is a modified glutamic acid residue, which is the key pharmacophore for the observed anticancer activity.

In the course of this study, several potentially novel Ahp-cyclic depsipeptides have been isolated from cyanobacteria as well as the previously identified loggerpeptins A-C and molassamide. Little is known about the release of these and other compounds into their environment or the role they may play in situ as chemical defense. Seawater surrounding field collections of cyanobacteria was collected and analyzed to determine which peptides were released into the seawater. Loggerpeptin A and Molassamide were detected in the seawater, indicating cyanobacteria release these compounds, yet not Loggerpeptin B, C, or Kurhahamide which were detected in the organic extract. While the exact role of these compounds remains to be fully characterized, they may function as digestion inhibitors in crustacean predators whose primary digestive enzymes are serine proteases.

The second project was to examine the chemical communication of crop species Brassica oleracea var. Capitata (cabbage) and Brassica rapa subsp. Rapa (turnips). Plant roots play a vital role in nutrient acquisition, ensuring the uptake of water and nutrients from the soil. These same roots secrete a mixture of small molecules into the surrounding soil which is called the root exudate. The chemical composition of root exudates consists of primary metabolites (those needed for survival) such as sugars, proteins, and organic acids, and to a lesser extent, secondary metabolites such as phenols and flavonoids. This chemical mixture is key in identity recognition and resource competition leading to the detection of predators and competitors or cooperative behaviors between related individuals.

The observable behavior and root mass differences of kin recognition has been well characterized; however, the signaling molecules involved remain understudied. A targeted metabolomics GC/MS study was conducted analyzing the polar metabolites in soil samples to investigate root exudate composition under competition. Identification of the chemicals involved can provide key insights into the chemical nature of identity recognition and competition among different plants.

The natural world operates through chemical signaling. The small molecules released by plants and marine cyanobacteria directly influence the behavior and survival of neighboring organisms. This study has advanced the understanding of chemical communication and provides novel insight into these interactions.

Pages

95

Available for download on Saturday, March 11, 2023

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