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Title: Total synthesis of CPI-2081, breitfussin B and synthetic studies towards myriastramide C and goadsporin
Author: Liu, Ke
ISNI:       0000 0004 5371 3880
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2015
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available