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Document Type

Dissertation - University Access Only

Award Date

2014

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Advisor

Fathi T. Halaweish

Abstract

Natural products have always been noted as a valuable source for drug discovery, and many of the currently available drugs have been derived directly or indirectly from natural products. Saudi Arabia has one of the richest areas of biodiversity in the Gulf, which consists of an admixture of plant species from Asian, African, and Mediterranean regions. Saudi flora contains 2,250 plant species distributed in 142 families; among these, more than 1,200 species are expected to have medicinal uses. Several plant families among Saudi flora have been reported to have medicinal properties, such as some species of the Cucurbitaceae family, which are commonly used in Saudi folk medicine. Cucumis prophetarum var. prophetarum (Cucurbitaceae ), which is locally called Shari-al-deeb, is commonly used in Saudi folk medicine for the treatment of liver disorders. Bioassay-guided fractionation and purification were used to isolate the main active constituents of Cucumis prophetarum var. prophetarum frutis. All fractions, subfractions, and pure compounds were screened for their anticancer activity against six human cancer cell lines: breast (MCF7, MDA-MB-231), colon (HCT-116), ovarian (A2780/ A2780CP), and liver (HepG2). The greatest cytotoxic activity was found to be in the ethyl acetate fraction, resulting in the isolation of five cucurbitacin compounds: cucurbitacins E, B, D and Q, as well as hexanorcucurbitacin D. These compounds were structurally elucidated using NMR spectroscopy, mass spectral analyses, and x-ray crystallography. Among the cucurbitacins that were isolated and tested, cucurbitacins B and E showed potent cytotoxicity activities against all six human cancer cell lines. More interestingly, human breast cancer cell lines were found the most sensitive to cucurbitacins. These findings encouraged us to target the estrogen receptor (ER) using a steroidal scaffold enriched with functionalities related to cucurbitacins, since ER is the most frequently found biomarker in the breast cancer tissues. A total of seventeen novel estrone analogs enriched with cucurbitacin-like functionalities were synthesized and their ability to bind to the ERs were studied using molecular modeling and ER competitive-binding assay. The estrogenic, cytotoxic, and antiestrogenic activities of these estrone analogs were examined using human breast cancer cell line MCF-7. The biological evaluation of these estrone analogs demonstrated that LA-10 and LA-7 possess potent inhibition of cell growth stimulated by estradiol, suggesting that they may have potential for treating breast cancer. Investigation of the antiviral activity of cucurbitacins against bovine viral diarrhoea virus (BVDV) and hepatitis C virus (HCV) was also conducted. The potential anti-BVDV activities of nine cucurbitacin compounds were evaluated using lactate dehydrogenase (LDH) assay, virus yield reduction assay, quantitative real-time RT-PCR, and Immunofluorescence staining. In addition, the effects of cucurbitacins B, D, and E on HCV replicon replication in Huh-7.5 cells were examined. Our data showed the potential inhibitory effect of cucurbitacins B, E, and D on BVDV and HCV replicon, suggesting that might serve as potential antiviral agents. To the best of our knowledge, this is the first report investigating the antiviral effects of cucurbitacins against BVDV and HCV.

Library of Congress Subject Headings

Cucumis Cucurbitaceae
Antiviral agents
Antineoplastic agents
Medicinal plants -- Saudi Arabia

Description

Includes bibliographical references (pages 164-168)

Format

application/pdf

Number of Pages

214

Publisher

South Dakota State University

Rights

In Copyright - Non-Commercial Use Permitted
http://rightsstatements.org/vocab/InC-NC/1.0/

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