Electronic Theses and Dissertations

Author

Lu DaiFollow

Date of Award

1-1-2019

Document Type

Thesis

Degree Name

M.S. in Pharmaceutical Science

First Advisor

Chalet Tan

Second Advisor

Walter G. Chambliss

Third Advisor

Mahmoud ElSohly

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

Artemisinin is currently used as an antimalaria drug. Studies have shown its monomeric form exhibited promising anticancer effects by inhibiting the proliferation, inducing apoptosis, and increasing oxidative stress of tumor cells. Recently, several dimeric forms of artemisinin have been synthesized with more potent anticancer activity. In this study, nine dihydroartemisinin dimers with diversely functionalized linkers exhibited similar cytotoxicity against human breast adenocarcinoma MDA-MB-231 in vitro. Among these nine DHA dimers, DHA dimer oxime was selected for further anticancer activity and pharmacokinetic study. Our preliminary study shothat DHA dimer oxime displayed more than a 10-fold increase of antiproliferation effect over its monomeric forms. DHA dimer oxime inhibited the growth of eight tested cancer cell lines and reduced cell proliferation at submicromolar concentrations. It was also suggested DHA dimer oxime combination with gemcitabine, a standard treatment for advanced pancreatic cancer, had yielded a synergistic anticancer effect in selected cell lines compared to the mono-treatment. Furthermore, DHA dimer oxime displayed longer half-life to its monomeric form DHA in mice, remaining above the median IC50 for pancreatic cancer cells for 4h after oral administration. Together, this study demonstrated the potential use of DHA dimer oxime as an anticancer therapeutic candidate.

Available for download on Wednesday, August 31, 2022

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