New approaches to combating drug resistance via saturated chemical architectures

Hind, Jasmine 2025. New approaches to combating drug resistance via saturated chemical architectures. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Tamoxifen, an aryl containing tetrasubstituted olefin, is an essential drug used to treat breast cancer. Despite its clinical success, intraindividual di;erences in plasma concentration of non-therapeutic metabolites can cause variation in tamoxifen’s e;icacy and could contribute to acquired tamoxifen resistance. One approach to address this issue includes the introduction of a benzene bioisostere that has an improved metabolic stability. An example of a C(sp³)-rich benzene bioisostere that may o;er improved metabolic stability is cubane, a highly strained cage structure first synthesised by Eaton and Cole. Consequently, in this thesis, we aimed to synthesise cubane derivatives of tamoxifen as a method to improve its metabolic profile. Several synthetic strategies were explored to construct a tetrasubstituted olefin bearing a cubane sca;old, ultimately leading to the successful preparation of a cubane-containing derivative of tamoxifen. In addition, bioisosteric replacement of benzene for cubane in pharmaceuticals has primarily been used to mimic terminal or para-substituted benzene rings, arising from the lack of general synthetic methods for the functionalisation of cubane. Given the prevalence of phenols in pharmaceuticals, it is noteworthy that synthetic routes to cubanols are virtually unknown. We postulated that the Bayer-Villiger rearrangement of cubane ketones, with a subsequent ester hydrolysis, could readily provide access to functionalised cubanols for applications in medicinal chemistry. Initially, we determined how steric and electronic factors influence the migratory aptitude of functionalised cubanes. We also demonstrate the synthetic utility of the hydrolysis of cubyl acetates to yield cubanols; this strategy was successfully applied to two analogues of the biologically active compound resveratrol.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Chemistry
Date of First Compliant Deposit:	23 February 2026
Last Modified:	23 Feb 2026 17:11
URI:	https://orca.cardiff.ac.uk/id/eprint/185132

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