Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Clinical-Bioanalytical Chemistry

Department

Chemistry

First Advisor

Su, Bin

Subject Headings

Analytical Chemistry, Biochemistry, Biology, Biomedical Research, Organic Chemistry, Pharmacology

Abstract

Project I: Chemotherapeutic drugs have many side effects that are undesirable and are highly toxic. Therefore, there is a growing need for the development of drugs with enhanced efficacy, specificity, and potency to provide cancer patients with a better prognosis. It was discovered that a member of the Receptor Tyrosine Kinase family, EphA2, may prove to be a viable target in developing anti-cancer agents. In the presence of its ligand, EphA2 receptor is responsible for apoptotic and anti-migratory activity. However, in the absence of ligand, EphA2 is able to stimulate cell migration and therefore tumorigenic activity. These conflicting roles of EphA2 and the upregulation of this receptor that is seen in many cancers have provided a novel strategy in designing therapeutic agents. Therefore, small molecules can be used to stimulate ligand-dependent pathways of EphA2 that induce anti-migratory and anti-proliferative effects in cancer cells in order to inhibit metastasis and tumor progression. A small molecule, doxazosin, was identified as an EphA2 agonist in a recent study. It demonstrated positive results in that its actions were similar to those of the natural ligand. Subsequently, a library of compounds was generated using doxazosin as the lead compound in order to improve its activity. These compounds were tested for their activity in stimulating EphA2 receptor. Two of them showed improved activity compared to doxazosin while mimicking a mechanism similar to the native ligand. The structure activity relationship of these derivatives, the in vitro mechanisms and pharmacokinetic profiles were also analyzed, which provides a basis for further optimization and subsequent in vivo studies of these compounds in the future. Project II: Copalic acid which is one of the diterpenoid acids in copaiba oil inhibited the chaperone function of ¿-crystallin and heat shock protein 27 kDa (HSP27). It also showed potent activity in decreasing the level of an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment. In order to develop potent drug candidates to decrease the AR level in prostate cancer cells, copalic acid analogs were synthesized. Using AR level as a readout 15 copalic acid analogs were screened, which showed that two of those compounds were much more potent than copalic acid. They inhibited AR positive prostate cancer cell growth in a dose-dependent manner. Furthermore, they also inhibited the chaperone activity of a-crystallin.

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