Electronic Theses and Dissertations

Date of Award

2017

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

Mitchell A. Avery

Second Advisor

Hoang Le

Third Advisor

Mahmoud Elsohly

Relational Format

dissertation/thesis

Abstract

The prevention and cure of malaria is difficult as it thrives under poor socio- and pharmacoeconomic conditions in third world, tropical and subtropical regions. It is a parasitic disease spread through the bite of an infected Anopheles mosquito. In humans, malaria can be caused by several Plasmodium species that include: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. The natural product artemisinin is a sesquiterpene lactone with an endoperoxide bridge isolated from the Chinese annual herb qinghao (Artemisia annua L or sweet wormwood). The relatively stable endoperoxide bridge is essential for their antimalarial activity. The synthesis of rac-6-Desmethyl-5β–hydroxy-D-secoartemisinin (a 1,2,4-trioxane) afforded a starting point upon which to conduct heretofore unexplored structure-activity relationships (SAR) about the C5 position. Additionally, as the C4 position is quintessential, via a C4 radical, to issues related to the molecular details of the mechanism of action of artemisinin, C5 derivatives were hypothesized and synthesized in order to test the effect of stabilization of the C4 radical. Previous studies from the literature of separate enantiomeric peroxides revealed that chirality was unimportant for bioactivity. It was felt that this could not be true in all cases because clear bioorganic and biological evidence for the intermediacy of protein receptors exists. By separating two Mosher ester diastereomers of the title compound followed by saponification into the (3R, 5R, 5aR, 9aS) and (3S, 5S, 5aS, 9aR) enantiomeric alcohols. It was found that all activity was associated with the (3R, 5R, 5a R, 9aS) diastereomer. This mirror image overlays with the x-ray structure of the natural product, R-(+)-artemisinin (the 3 R trioxane). This is logical as the mechanism of action (MOA) of artemisinin and related 1,2,4-trioxanes appears to be related to protein binding followed by a Fe(II)-mediated C4 radical hypothesized to react covalently with a plasmodial SERCA cysteine moiety, blocking the SERCA Ca-channel. This radical is produced by an O1-O2/C3-C4 ring cleavage, suggesting that logical modifications at C5 would be expected to test this aspect of the proposed MOA and provide additional SAR to complement known modifications elsewhere in the backbone of the natural product.

Concentration/Emphasis

Emphasis: Medicinal Chemistry

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