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Towards The Total Synthesis Of Withanolide E And Physachenolide C
Anees, Muhammad
Anees, Muhammad
Publication Date
2020
End of Embargo
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The University of Bradford theses are licenced under a Creative Commons Licence.
Peer-Reviewed
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Institution
University of Bradford
Department
Institute of Cancer Therapeutics. School of Pharmacy and Medical Sciences. Faculty of Life Sciences
Awarded
2020
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Abstract
Withanolides are a class of ergostane natural products found in plants of family Solanaceae.
Plants of this family are used in traditional medicine in Asia and South America. Recently, a
series of 17β-hydroxy withanolides were identified from high-throughput screens as
inhibitors of androgen-induced changes in gene expression of prostate cancer cells.
Therefore, these compounds may have important applications as new therapies against
prostate cancer. We have devised a synthetic route to members of this family and their
analogues which allows stereoselective introduction of C14, C17 and C20 hydroxyl groups in
separate steps. This will allow preparation of differentially hydroxylated analogues so as to
identify which contributes to the potency and thus gain a better understanding of the SAR of
this class of bioactive molecules. As part of this we have shown that the stereochemical
outcome of the epoxidation of Δ 14-15 cholestanes with m-CPBA is controlled by the steric bulk
of a C17 substituent. When the C17 is in the β configuration, the epoxide is formed on the α
face, whereas if the C17 is trigonal (flat) or the substituent is in the α configuration, the epoxide is formed on the β face. The presence of a hydroxyl substituent at C20 does not
influence the stereochemical outcome of the epoxidation. We have successfully introduced
aldehyde functionality to the lateral side chain 14 hydroxyl compound. This aldehyde
compound is a key intermediate from which many of the withanolides can be made. We
have also investigated the introduction of a hydroxyl at the C18 as an entry into the
physachenolides. Finally, we have carried out an assessment of the potency of the
synthesised compounds against hormone-insensitive prostate cancer cell line, PC-3.
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Type
Thesis
Qualification name
PhD