Synthesis and Biological Evaluation of Tyrphostins As Anticancer Agents

Montgomery, Gerard John (1995) Synthesis and Biological Evaluation of Tyrphostins As Anticancer Agents. PhD thesis, University of Glasgow.

Abstract

Recent developments in molecular biology have led to a greater understanding of signalling mechanisms which are overexpressed or distorted in the cancer cell, resulting in the identification of a number of new molecular targets for cancer chemotherapy. Protein Tyrosine Kinases (PTKs) are enzymes which play an important role in the signal transduction pathways leading to mitogenesis. Growth factors, such as epidermal growth factor (EGF) are responsible for stimulating cells to synthesise DNA prior to mitosis. The EGF receptor, which is present at elevated levels in certain cancer cells, has been shown to display PTK activity. Tyrphostins are low molecular weight molecules which are structurally similar to tyrosine. These have been shown to display PTK inhibition activity. The earliest reported tyrphostins such as (a) were based upon a benzylidenemalononitile nucleus, but more recently a number of tyrphostins containing a 5-membered heterocyclic nucleus (b) have been reported. Tyrphostins containing a nitrothiophene fragment (c) were prepared using standard methodology. These compounds were shown to display excellent in vitro growth inhibition in cells with a high EGF concentration. More detailed studies later showed that a number of these compounds were not selective for the EGF receptor, and instead displayed wide-spectrum cytotoxicity by an unknown mechanism. The crystal structure of one tyrphostin was solved, showing that the aromatic and cyano groups are cis across the extra-annular double bond. Previous studies had shown that analogues of misonidazole (d) which contained a nitrothiophene group (e) possessed the ability to become reduced to cytotoxic species in hypoxic tumour cells, which have a low oxygen saturation. The reduction potentials of a number of nitrothienyl tyrphostins were measured, and some of these fell within the parameters required for in vivo bioreduction. Pyridyl and quinolyl tyrphostins such as (f) and (g) have been reported to display interesting biological profiles. In particular, 2- and 4-substituted quinolines were particularly active, and this may be perhaps due at least in part to substitution at these electropositive centres. Substitution at the 3-position gave rise to a series of inactive compounds. In order to extend the study of this structure-activity relationship, a series of 6-, 7- and 8-quinolyl tyrphostins (h) were synthesised. Antibody-Directed Enzyme Prodrug Therapy (ADEPT) is a sophisticated method to deliver cytotoxic agents at their preferred site of action. An antibody which recognises surface antigens on a cancer cell also possesses an enzyme which hydrolyses a prodrug molecule such as (i) and leads to the release of the drug molecule. A methodology to synthesise such a prodrug was investigated, but it was not possible to complete the urea linkage between L-glutamate and the benzene ring by attempting to generate an isocyanate at either of the amino groups in the starting materials.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: David J Robins
• Keywords: Organic chemistry, Pharmacology
• Date of Award: 1995
• Depositing User: Enlighten Team
• Unique ID: glathesis:1995-75626
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 19:15
• Last Modified: 19 Nov 2019 19:15
• URI: https://theses.gla.ac.uk/id/eprint/75626