Alkaloid-like molecules as AChE inhibitors and anticancer agents for therapeutic relief of alzheimer's disease and cancer
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Due to the prevalence of alkaloids in the chemical drug space and the broad range of biological properties held by the Aristotelia alkaloids, including anticancer properties, a library of structurally similar alkaloid-like compounds has been synthesised, containing the 3-aza-bicyclo[3.3.1]nonane architecture, in order to explore the cytotoxicity of it and its derivatives. The 3-aza-bicyclo[3.3.1]nonane core was obtained via the bridged Ritter reaction with (-)-β-pinene and various nitriles to afford 18 compounds (Chapter 2). Several of the compounds obtained from the bridged Ritter reaction were derivatised to give an additional 17 compounds (Chapter 3). The information obtained from these reaction outcomes, were used to further understand the bridged Ritter reaction mechanism. X-ray crystallography was used for analysis of the projection of the scaffold and substituents within the 3D space of the crystal lattice to further understand the reactivity of the synthesised scaffolds. The library of alkaloid-like compounds was tested for their biological properties. The breast cancer cell lines MDA-MB-231 and MCF-7 were investigated due to in-house data that showed activity for a related series of compounds (Chapter 4). The MDA-MB-231 cell line was tested in-house and 3 of 28 compounds showed significant activity in the reduction of cell viability, however, it is believed that they possess general toxicity, as opposed to having a cytotoxic nature. This library was deemed not viable for developing as cytotoxic agents within this project. Acetylcholine esterase (AChE) was chosen as an alternative target to be screened against (Chapter 5). Two complementary assays were used to determine the activity were 9 of the 27 tested compounds showed weak activity. SAR data and molecular modeling was used to develop a rational drug design approach to synthesise an improved inhibitor. Two of the designed compounds were synthesised and evaluated for their AChE inhibition properties and both showed relative increase in activity compared to their precursors. In addition to the docking studies used to guide the design of improved AChE inhibitors, molecular modeling was utilised to assess the drug-like properties and ADMET descriptors for each of the synthesised compounds. Lastly, broad screening of the biological properties of a selection of the synthesised compounds is currently being investigated by the services of the Lily OIDD program with 16 of the 31 submitted compounds are currently undergoing screening and results from five compounds have been returned so far.
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