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The synthesis of 1,2,4-triazine-3,6-diones and the structure-based design and synthesis of HIV-1 protease inhibitors

The synthesis of 1,2,4-triazine-3,6-diones and the structure-based design and synthesis of HIV-1 protease inhibitors
The synthesis of 1,2,4-triazine-3,6-diones and the structure-based design and synthesis of HIV-1 protease inhibitors

The heterocyclic structure 1,2,4-triazine-3,6-dione is chosen as a peptidomimetic analogue of cyclic dipeptides (diketopiperazines), and its potential as a novel scaffold for drug discovery is assessed.

A two-step synthesis towards 1,2,4-triazine-3,6-diones, producing a range of 20 novel 1,2,4-triazine-3,6-diones is described.  Boc protected hydrazines and amino acid methyl esters are reacted with triphosgene in a one-pot reaction to give a range of over 30 novel semicarbazides.  The cyclisation of these semicarbazides under thermal and microwave conditions is explored.  Two novel 3-aminohydantoins are also isolated and the assignment of the two heterocyclic structures according to their spectral data is discussed.  The 1,2,4-triazine-3,6-diones are tested for biological activity against breast cancer cells and their improved activity compared to the cyclic dipeptide cyclo(Phe-Pro) is discussed.

Mechanistic investigations into the reaction of α-hydroxy esters with Mitsunobu reagents are described.  it is shown that the α-hydroxy esters are oxidised to α-keto esters following the proposed literature mechanism.  In addition this work has provided a novel synthesis of 1,2,3-oxadiazole-2,3-dicarboxylic esters from α-keto esters and 1,2-diketones.

Chapter two describes the structure-based design of the HIV-1 protease inhibitor core Phe-Pro diol and the synthesis towards this structure.  The coupling of the two amino acid derived fragments is explored using Julia, modified Julia and Hoppe coupling procedures.  The advantages and sensitivities of these three methods are compared and discussed.

University of Southampton
Radford, Sally Katherine
70636ab5-599e-4937-bef2-6369a2c9034d
Radford, Sally Katherine
70636ab5-599e-4937-bef2-6369a2c9034d

Radford, Sally Katherine (2007) The synthesis of 1,2,4-triazine-3,6-diones and the structure-based design and synthesis of HIV-1 protease inhibitors. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The heterocyclic structure 1,2,4-triazine-3,6-dione is chosen as a peptidomimetic analogue of cyclic dipeptides (diketopiperazines), and its potential as a novel scaffold for drug discovery is assessed.

A two-step synthesis towards 1,2,4-triazine-3,6-diones, producing a range of 20 novel 1,2,4-triazine-3,6-diones is described.  Boc protected hydrazines and amino acid methyl esters are reacted with triphosgene in a one-pot reaction to give a range of over 30 novel semicarbazides.  The cyclisation of these semicarbazides under thermal and microwave conditions is explored.  Two novel 3-aminohydantoins are also isolated and the assignment of the two heterocyclic structures according to their spectral data is discussed.  The 1,2,4-triazine-3,6-diones are tested for biological activity against breast cancer cells and their improved activity compared to the cyclic dipeptide cyclo(Phe-Pro) is discussed.

Mechanistic investigations into the reaction of α-hydroxy esters with Mitsunobu reagents are described.  it is shown that the α-hydroxy esters are oxidised to α-keto esters following the proposed literature mechanism.  In addition this work has provided a novel synthesis of 1,2,3-oxadiazole-2,3-dicarboxylic esters from α-keto esters and 1,2-diketones.

Chapter two describes the structure-based design of the HIV-1 protease inhibitor core Phe-Pro diol and the synthesis towards this structure.  The coupling of the two amino acid derived fragments is explored using Julia, modified Julia and Hoppe coupling procedures.  The advantages and sensitivities of these three methods are compared and discussed.

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Published date: 2007

Identifiers

Local EPrints ID: 466299
URI: http://eprints.soton.ac.uk/id/eprint/466299
PURE UUID: cf1ea753-8fc8-4951-abdb-387ba4110bab

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Date deposited: 05 Jul 2022 05:07
Last modified: 16 Mar 2024 20:37

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Author: Sally Katherine Radford

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