Date of Award

12-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Medicinal Chemistry

Research Advisor

Wei Li, PhD

Committee

Duane D. Miller, PhD; Darryl L. Quarles, PhD; Zhousheng Xiao, PhD; Chao-Yie Yang, PhD; Junmin Yue, PhD

Keywords

Drug design;Sabizabulin conjugate

Abstract

Cancer and osteoporosis are two commonly diagnosed disease around the world which poses major health threat. In this thesis, we provide the background information to two types of cancers, namely ovarian cancer and liver cancer, as well as osteoporosis, and our approach for the treatment of the diseases. In chapter one, we discussed the background information about the diseases. The cause and the current treatment options are discussed, providing the basis for the chapters written later. In chapter two, we focused on the treatment of hepatocellular carcinoma. To construct the drug, we utilized a technique called small molecule drug conjugate, which combines the potency of the payload and the selectivity of the targeting moiety. We designed the conjugate using a potent tubulin inhibitor, veru-111, a targeting moiety reported in the literature, and a glutathione responsive linker, and then, successfully synthesized the compound, waiting for further biological testing. In chapter three, we described our findings on the compound HL142 for the treatment of ovarian cancer. Epithelial to mesenchymal transition is a central mechanism related to ovarian cancer metastasis and chemoresistance, and the protein, ASAP1, is essential for the process. By searching the literature, we found a compound, luminacin D, which may inhibit the protein. Thus, HL142, the analogue of which, was tested in the ovarian cancer model in vitro and in vivo. The results suggested HL142 as a potent compound for inhibiting ovarian cancer tumor growth, metastasis and invasion, making it a good starting point for further modifications. In chapter four, we described the structure based drug design on the compound, MS, which was previously identified in the in silico screening. The SAR of which was extensively studied, and several compounds were identified to have better potency than the lead compound in the in vitro study, which might be further modified into drugs treating osteoporosis. In conclusion, using different approaches, we successfully found numerous com- pounds for the treatment of different diseases, which may provide a solid base for the development of brand new drugs.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0003-0120-3582

DOI

10.21007/etd.cghs.2023.0645

Additional Files
2023-032-Li-DOA.pdf (286 kB)
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