Montgomery, Laura Jane (2008) Investigations of the biosynthesis and biomimetic synthesis of bioactive natural products. PhD thesis, University of Warwick.

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Abstract

This thesis describes work towards the biomimetic synthesis and understanding the
biosynthesis of two families of natural products: prodiginines and quartromicins.
Prodiginines are a large family of red pigmented tripyrrole antibiotics. Although they
have not been used clinically, the promising anti-cancer, immunosuppressive and antimalarial
activity they display at non-toxic doses has generated renewed interest in their
utilisation. The synthesis of an analogue of the proposed pyrrole-2-carboxyl-RedO
intermediate in prodiginine biosynthesis has been achieved. The resulting NAC
thioester and analogues of it have been used to investigate the prodiginine biosynthetic
pathway in Streptomyces coelicolor, and to examine the production of prodiginine
analogues by mutasynthesis.
Quartromicins, novel anti-viral antibiotics, are a structurally unique group of
spirotetronate natural products produced by Amycolatopsis species. They are unusual
symmetric macro cyclic compounds which possess a 32-membered carbocyclic structure
with four spirotetronic acid units connected by enone or dienone linkers in a head-to-tail
fashion. These macrocyclic compounds are intriguing because they have alternating
endo- and exo- spirotetronic acid units, with the opposite "comers" being identical.
Although the quartromicins have therapeutic potential, very little is known about their
biosynthesis. In this research a biosynthetic pathway to the quartromicins has been
proposed based on hypothetical pathways to related natural products. The synthesis of
the two putative key intermediates in quartromicin biosynthesis has been achieved. An
improved method for the synthesis of exomethylene tetronates has been developed, and novel rearrangements have been discovered. The two putative key intermediates have
been used to investigate the biomimetic synthesis of the carbon skeleton of the
quartromicin algycone, and mass spectrometric evidence for formation of homo- and
heterodimers, and a heterotetramer of the key intermediates has been obtained.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	R Medicine > RS Pharmacy and materia medica
Library of Congress Subject Headings (LCSH):	Biomimetics, Antibiotics -- Synthesis, Streptomyces coelicolor, Bioactive compounds
Official Date:	March 2008
Dates:	Date Event March 2008 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Challis, Gregory L.
Sponsors:	Engineering and Physical Sciences Research Council (EPSRC)
Extent:	xxiv, 202 leaves
Language:	eng

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