Appraisal of breast cancer drugs and their precursors by Signal Amplification By Reversible Exchange

Zukowicz, Filip (2021) Appraisal of breast cancer drugs and their precursors by Signal Amplification By Reversible Exchange. Masters by Research thesis (MSc), Manchester Metropolitan University.

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Abstract

The purpose of this study was to develop the application method of Signal Amplification By Reversible Exchange (SABRE) hyperpolarization to a pharmaceutically approved drug Letrozole. Letrozole is a drug used to treat breast cancer. It belongs to the family of drugs called aromatase inhibitors. Aromatase is the cytochrome P450 enzyme complex, which convert androgenic steroids into estrogenic steroids. Around 70% of breast cancer cells are sensitive to estrogen (or estrone - a potent endogenous estrogen), which contributes to the initiation, promotion and progression of breast cancer. Firstly, this study focused on full characterisation of 4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (letrozole) and on synthesis and full characterisation of the derivatives that lead up to its structure. Secondly, it was essential to develop a quantitative method of detection of all the compounds using bench top 1H Nuclear Magnetic Resonance (NMR) spectrometry. Thirdly, the largest part of the project was investigating the feasibility to hyperpolarize the compounds, focused mainly on letrozole, due to the presence of triazole functional group present in all of them. Hyperpolarization is known to lower detection limits, offer quicker and better analysis results, and cut costs when compared to regular NMR analysis. Due to the ease of use and the low costs, SABRE was the method used to achieve hyperpolarization of the compounds. The hyperpolarization of compounds 1,2,4-triazole, 1-methyl-1H-1,2,4-triazole, 1-benzyl-1,2,4-triazole, 4-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile, and letrozole were successful, with 1,2,4-triazole having the highest peak enhancement of -54 following polarization transfer in a 65 G field, with letrozole, which is significantly more complex in terms of its molecular architecture, having the lowest peak enhancement of -7. Only the biggest peak enhancements have been recorded for each molecule. The fact that SABRE hyperpolarization produced negative signal improvement in the 1H NMR spectrum of letrozole suggests, that the clinically approved drug could be hyperpolarized, and potentially used in molecular imaging as a breast cancer imaging agent.