Total Synthesis of CPI-2081, Breitfussin B and Synthetic Studies Towards Myriastramide C and Goadsporin

Liu, Ke (2015) Total Synthesis of CPI-2081, Breitfussin B and Synthetic Studies Towards Myriastramide C and Goadsporin. Doctoral thesis, University of East Anglia.

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Abstract

Natural products have been the source and inspiration of numerous drugs. However, as
they need to be isolated from natural sources, they are often obtained in minute
quantities. Hence, total syntheses of natural products and their analogues give us a
better chance to look into their biological activities and perform SAR studies for drug
discovery.
During my doctoral tenure I have synthesised a number of natural products and also
some fragments. CPI-2081, a 2:1 mixture of two pentapeptides 1.8 and 1.9, were
isolated from Streptomyces species NCIM 2081. These peptides are potent inhibitors
(IC50 36.9 ± 1.8 nM) of the cysteine protease papain and inhibit cancer cell migration.
However it was not clear which peptide is responsible for the observed biological
activities. Both peptides have been prepared synthetically in our lab and they are being
tested.
Myriastramide C (2.23) is a modified cyclic octapeptide isolated from M. clavosa. The
complete series of myriastramides A-C represent the first peptide metabolites isolated
from M. clavosa. They were assumed to be cytotoxic, however myriastramide A was
found inactive against 10 different human cancer cell lines. Myriastramides B and C
were isolated in insufficient quantities so similar tests cannot be performed.
Furthermore, the stereochemistry of the tryptophan residue in myriastramide C was not
confirmed due to insufficient material isolated. Myriastramide C has been synthesised
in our laboratory using L-tryptophan, however a mixture of products were obtained due
to the two proline residues in the peptide. A pure product was purified by our
collaborator and further NMR and biological studies is underway.
Goadsporin (3.14) is a linear oligopeptide that was isolated in 2001. Its unique structure
contains 19 amino acids, six of which are cyclised to form four oxazole and two
thiazole rings. Goadsporin was found to be active specially in streptomycetes, with the
ability to promote morphogenesis and secondary metabolism. It can also promote
antibiotic production. The synthesis of this natural product was challenging, and
I
I
unfortunately with the limited time of my PhD study, we did not complete the total
synthesis. However, we have synthesised several fragments of it, and they are going to
be tested in the future.
Breitfussin B (4.35) was first isolated in 2007 from the sample of Thuiaria breitfussi
collected from Bear Island. Its highly unsaturated nature prevented its structure
elucidation until 2012: Hanssen et al. proposed a structure using a combined atomic
force microscopy and computational approach. However no biological activity was
reported. The total synthesis of breitfussin B was completed in our lab, and tested for its
antimicrobial ability. Further biological studies are underway.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Mia Reeves
Date Deposited: 29 Jan 2016 11:25
Last Modified: 29 Jan 2016 11:25
URI: https://ueaeprints.uea.ac.uk/id/eprint/56872
DOI:

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