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Title: Solid-phase-based synthesis and biological evaluation of quinoxaline antibiotics and structural analogues
Author: Dawson, Simon Jonathan
ISNI:       0000 0004 2683 4986
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2009
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Triostin A N-demethylated (TANDEM) is a synthetic analogue of the natural product triostin A. Both compounds belong to an extended family of quinoxaline- and quinoline-functionalised cyclic octadepsipeptides, with an ability to bifunctionally intercalate DNA. TANDEM has recently been synthesised by Malkinson and coworkers by a solid-phase-based methodology. This strategy was chosen as it potentially allowed rapid synthesis of analogues where each amino acid residue could be altered, or the natural symmetry removed. The aims of this project were: 1) To further increase the efficiency of TANDEM synthesis, either by optimising various key stages of the existing method (e.g. depside bond formation, macrolactamisation), or by designing an alternative synthetic route; 2) To synthesise the natural product triostin A, and the analogue TACDEM (triostin A cysteine demethylated) using a solid-phase-based methodology; 3) To synthesise a series of TANDEM chromophore analogues, in order to investigate key structure-activity relationships. Optimisation of on-resin depside bond formation was monitored using a retrospective RP-HPLC methodology, allowing quantitative assessment of yield using a range of reagents and solvents. In order to synthesise TANDEM entirely by a solid-phase methodology, a novel aminothioacetal-based resin linker was designed to immobilise the peptide via the side chain of cysteine. Although synthesis of the linker and a cyclic nonapeptide were successful, the synthesis of TANDEM was hampered by a number of factors, including peptide-resin aggregation and difficulties with C-terminal carboxyl deprotection. SPPS of the linear TACDEM precursor was found to lead to quantitative diketopiperazine (DKP) formation, and although this side-reaction was thought to be less serious in the synthesis of triostin A, neither compound could be prepared via this route. Ten chromophore analogues of TANDEM were synthesised via a solid-phase-based methodology, including examples where, for the first time, two different chromophores were installed on the same depsipeptide core. A bis-Z-protected precursor was also used to prepare a further two symmetrical analogues, introducing both chromophores in the final step.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available