Date Thesis Awarded

12-2022

Access Type

Honors Thesis -- Open Access

Degree Name

Bachelors of Science (BS)

Department

Chemistry

Advisor

Dana Lashley

Committee Members

Robert Pike

Randolph Coleman

Oliver Kerscher

Abstract

This thesis delineates two main projects: the first outlines the structure elucidation efforts toward a Diels-Alder adduct of a novel reaction for the synthesis of chimaphilin, a naphthoquinone-based natural product with apoptotic or antiproliferative activity in certain cancer cells1,2. The structure elucidation extends to derivatives of chimaphilin synthesized by the same cyclization reaction. While Diels-Alder reactions are usually regioselective, 1H-NMR and 13C-NMR of the adducts was inconclusive and indicated the possibility of regioisomer presence, with one regioisomer being chimaphilin (or derivatives). A multitude of crystallization methods were carried out in order to be able to analyze the products via X-ray crystallography. An unusual chimaphilin [2+2] cycloaddition dimer was discovered, indicating the correct positioning of the methyl group at C6 of the naphthoquinone scaffold. A phenyl derivative of chimaphilin was also crystallized to reveal a mixture of regioisomers with substituents positioned at C6 or C7 respectively.

The second project marks the auspicious beginnings of a Structure-Activity Relationship (SAR) study based on hit compound EVP4593, a known mitochondrial complex I (MCI) inhibitor3. The intention of this SAR study is the design of an improved MCI inhibitor for use as a potential anticancer agent. A series of derivatives of EVP4593 were synthesized, purified, and analyzed spectroscopically. Biological testing was conducted both in vitro on in-membrane NADH, succinate, and dNADH oxidases and on isolated bd-I and bd-II oxidases from Escherichia coli (E. coli) and in vivo against a genetic knockout library of >5100 Saccharomyces cerevisiae (S. cerevisiae) strains, revealing that the compound titled “H-EVP1” was the most potent inhibitor out of the tested EVP4593 derivatives and was possibly selective for MCI when compared to other oxidases.

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