Defense Date

5-30-2023

Graduation Date

Summer 8-5-2023

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Kevin Tidgewell

Committee Member

David Lapinsky

Committee Member

Marc Harrold

Committee Member

Jane Cavanaugh

Committee Member

Patrick Flaherty

Keywords

Cyanobacteria, Cancer, Sigma-2, Central nervous system, Breast cancer, Barbamide, Veraguamide, Marine cyanobacteria

Abstract

Cyanobacteria have been studied for over 50 years as a source of new antibiotics, antiviral, and anticancer drugs. The research described in this dissertation investigates marine cyanobacteria as a source of natural products with activity within the central nervous system and with cytotoxicity against breast cancer cells. Barbamide (1) is a known cyanobacterial metabolite that has been re-isolated from a variety of species and collection sites suggesting broad utility as a signaling molecule. Utilizing the psychoactive drug screening program, we screened barbamide for CNS activity and found that barbamide exhibited affinity for the kappa opioid receptor (KOR) and the sigma-2 receptor. Additionally, we isolated three veraguamide analogs from a cyanobacterial sample collected from Isla Mina in the Las Perlas Archipelago of Panama. Veraguamide C (2), veraguamide O (3), and veraguamide P (4) were determined to have affinity for the sigma-2 receptor as well as increased cytotoxicity for MDA-MB-231 TNBC cells compared to MCF-7 breast cancer cells. In order to further investigate the activity of the most potent cytotoxic agent (4), the total synthesis of 4 was proposed. After overcoming several synthetic challenges, the total synthesis was completed and was used for further biological evaluation and structure confirmation. Additionally, three analogs of 4 were synthesized in order to investigate some of the structure-activity relationships. These analogs were methoxy-veraguamide P (5), methoxy-veraguamide P amide (6) and veraguamide P amide (7). These compounds were screened for cytotoxicity and CNS activity. After isolation of multiple cyanobacterial natural products with CNS activity, an analysis was conducted on the bioactivity of our cyanobacterial fraction library to evaluate the effectiveness of our sample processing method in identifying active fractions. A new method for pre-fractionation was proposed to improve the detection of CNS active fractions. This research is an example of exploring the rich bioactivity found from marine cyanobacteria.

Language

English

Download

Share

COinS