Term of Award

Fall 2021

Degree Name

Master of Science in Biology (M.S.)

Document Type and Release Option

Thesis (restricted to Georgia Southern)

Copyright Statement / License for Reuse

Digital Commons@Georgia Southern License

Department

Department of Biology

Committee Chair

Vinoth Sittaramane

Committee Member 1

Shainaz Landge

Committee Member 2

Scott Harrison

Abstract

The zebrafish (Danio rerio) melanocyte system offers an informative and translational, high-throughput (HTP) model for preclinical drug discovery. High fecundity, rapid development and ex-vivo fertilization allow for rapid drug screens to be employed with large sample sizes. Similar neuro-development pathways and a high degree of homology to humans has established zebrafish as a keystone model of neurological disorders. Specifically, melanocyte physiology and melanogenesis have been tied to intracellular signal transduction pathways and catecholamine biosynthesis. As a result, phenotypic screens of melanocytes have proven useful for indicating physiological changes on a molecular level. The prevalence of zebrafish as a model in literature has generated a vast catalogue of comparable phenotype characterizations, making it an optimal candidate for HTP studies. In this study, two groups of novel small molecules were synthesized using green chemistry practices (3,4,6-trisubstituted pyridazines and ortho-substituted bisfunctionalized triazoles). Both groups have exhibited anticancer, antiviral and antidepressant properties, amongst others. Pyridazines and triazoles were assessed for their clinical potential by screening for toxicity and biological activity in zebrafish. It was found that pyridazines induce melanosome aggregation and analgesia in treated zebrafish - indicative of agonistic interaction with the alpha-2a adrenoceptor. Zebrafish treated with triazoles exhibited a depigmentation phenotype. Depigmentation was hypothesized to result from triazole induced tyrosinase inhibition, which was subsequently assessed via a biochemical inhibition assay – which exhibited a significant reduction in tyrosinase activity. Although both compound classes induced physiological changes, studies must be progressed to mammalian models to further characterize clinical potential and exact mechanisms of action.

OCLC Number

1414978067

Research Data and Supplementary Material

No

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