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Title: Synthesis of prenyl transferase inhibitors and histone deacetylase inhibitors
Author: Rioja, Alphonso S.
ISNI:       0000 0001 3519 5862
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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Simple monoterpenes and terpenoids such as limonene and perillyl alcohol have been reported to confer significant chemopreventive activity in rat and human carcinomas. A clinical study at Charing Cross Hospital highlighted a possible correlation between the isoprenoids ability to prevent protein-prenylation of small G-proteins (Ras) by inhibiting prenyl-protein transferase (enzyme) and their anti-cancer activity. An investigation into the family of terpenes and terpenoids (isoprenoids) with their correlation to chemoprevention was conducted. Since the inhibition of prenyl-protein transferase enzyme was believed to be integral to the anti-cancer activity of isoprenoids, a thorough examination of enzyme activity and different types of enzyme inhibition was performed. An in-depth analysis of farnesyl-protein transferase and geranylgeranyl (type I and II)-protein transferase was carried out, as these are the enzymes inhibited by terpenes and terpenoids, believed to result in their anti-cancer activity. A look at the known inhibitors of these enzymes in literature is assessed, and the production of a model designed to produce synthetic 'terpenoid' compounds capable of significant prenyl-protein transferase inhibition was created. From the model, a range of compounds encompassing short-chain monocyclic, long-chain mono-and bicyclic, and medium- to long-chain structures with a strongly polar terminus was produced, and evaluated with an in vitro enzyme inhibition assay to determine the potency of the compounds. Farnesol has been reported to cause apoptosis of cancerous cell lines, an investigation was performed with farnesol and two more compounds, (structurally similar to farnesol) to see whether these compounds could induce preferential apoptosis of various leukaemic cells. Histone deacetylation (HDAC) inhibition as a potential cancer therapy has been a recent discovery. Validation of a non-isotopic HDAC assay (HPLC) to determine HDAC inhibition for different compounds was conducted. The production of possible HDAC inhibitors based on the structure of trichostatin A was performed and the potency evaluated with an in vitro isotopic HDAC assay and a cancerous cell line proliferation assay.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available