An investigation into the mechanism of action of Amphiphilies with Antineoplastic properties
An investigation into the mechanism of action of Amphiphilies with Antineoplastic properties
A range of type I amphiphiles with molecular shape analogues to cytotoxic ether lipids like HDPC and ET-18-OMe were synthesised. These compounds were quaternary ammonium, polyethylene glycol and phosphate ester amphiphiles. Quaternary ammonium amphiphiles were synthesised by the Menschutkin reaction. Polyethylene glycol amphiphiles were synthesised using a phase transfer Williamson reaction developed in this study. Phosphate ester amphiphiles were synthesised from the reaction of halophosphates alcohols.
Each compound was tested for cytotoxic activity against the HL-60 cell line and a structure activity series was compiled. A correlation between increasing cytotoxic activity and increasing type I molecular shape was observed. Investigation of the aggregate properties of the type I amphiphiles showed that detergency was not a viable mechanism of action at the ED50 concentration.
A physico-chemico model for the mechanism of action of type I amphiphiles was investigated. Testing a hypothesis where type I amphiphiles are thought to modulate the stored elastic stress of cell membranes, preventing translocation of the CCT enzyme. Inhibiting CDP-choline synthesis and bulk de novo PC biosynthesis resulting in cell death through apoptosis.
Electrospray Mass Spectrometry was used to determine the composition of endogenous PC, PE and newly synthesised PC phospholipid fractions of both whole cells and nuclei. After incubation with type I amphiphiles decreases in total new PC synthesis were observed. Increases in the synthesis of type II phospholipids in the phospholipid fractions were also observed as predicted by the physico-chemico model under test.
University of Southampton
Dymond, Marcus Karl
4b9eae77-3e85-484d-919a-27e3a27b5658
2001
Dymond, Marcus Karl
4b9eae77-3e85-484d-919a-27e3a27b5658
Dymond, Marcus Karl
(2001)
An investigation into the mechanism of action of Amphiphilies with Antineoplastic properties.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
A range of type I amphiphiles with molecular shape analogues to cytotoxic ether lipids like HDPC and ET-18-OMe were synthesised. These compounds were quaternary ammonium, polyethylene glycol and phosphate ester amphiphiles. Quaternary ammonium amphiphiles were synthesised by the Menschutkin reaction. Polyethylene glycol amphiphiles were synthesised using a phase transfer Williamson reaction developed in this study. Phosphate ester amphiphiles were synthesised from the reaction of halophosphates alcohols.
Each compound was tested for cytotoxic activity against the HL-60 cell line and a structure activity series was compiled. A correlation between increasing cytotoxic activity and increasing type I molecular shape was observed. Investigation of the aggregate properties of the type I amphiphiles showed that detergency was not a viable mechanism of action at the ED50 concentration.
A physico-chemico model for the mechanism of action of type I amphiphiles was investigated. Testing a hypothesis where type I amphiphiles are thought to modulate the stored elastic stress of cell membranes, preventing translocation of the CCT enzyme. Inhibiting CDP-choline synthesis and bulk de novo PC biosynthesis resulting in cell death through apoptosis.
Electrospray Mass Spectrometry was used to determine the composition of endogenous PC, PE and newly synthesised PC phospholipid fractions of both whole cells and nuclei. After incubation with type I amphiphiles decreases in total new PC synthesis were observed. Increases in the synthesis of type II phospholipids in the phospholipid fractions were also observed as predicted by the physico-chemico model under test.
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Published date: 2001
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Local EPrints ID: 464756
URI: http://eprints.soton.ac.uk/id/eprint/464756
PURE UUID: 93dbd03f-44ee-417d-901b-5d5bea065861
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Date deposited: 04 Jul 2022 23:59
Last modified: 16 Mar 2024 19:43
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Author:
Marcus Karl Dymond
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