Synthesis and antibacterial profiling of dehydroamino acid containing argyrin analogues

Yang, Lei (2018) Synthesis and antibacterial profiling of dehydroamino acid containing argyrin analogues. PhD thesis, University of Nottingham.

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The argyrins are a family of macrocyclic heptapeptides isolated from the marine myxobacterium Archangium gephyra. Among them, argyrin A 1.1 and B 1.2 displayed potent antibacterial activity against multidrug resistant Gram-negative human pathogen Pseudomonas aeruginosa and Burkholderia multivorans. The bacterial elongation factor G (EF-G) was identified as the conserved cellular target of argyrin A and B in P. aeruginosa.

The aim of this thesis was to synthesise argyrin analogues with improved antibacterial activity and therefore contributes to the structural activity relationship (SAR) of such analogues towards P. aeruginosa and B. multivorans. The total synthesis of argyrin analogues was achieved through a Fmoc/tBu solid-phase peptide synthesis followed by a solution phase head-to-tail macrocyclisation.

The key building blocks, N-Boc-thiazole dipeptide 1.29, substituted L-tryptophan analogues 1.44 and β-substituted Fmoc-dehydroamino acids were obtained by new synthetic procedures. In addition to the previously reported modified Hantzsch’s approach, synthesis of the N-Boc-thiazole dipeptide 1.29 was also achieved by MnO2-mediated oxidation of thiazolidine, pre-formed by condensation of L-cysteine with pyruvaldehyde, to thiazole. The asymmetric synthesis of substituted L-tryptophan analogues 1.44 was accomplished through the application of glycine-Ni(II) Schiff base 1.40, which allowed the synthesis of argyrin analogues with various substituted L-tryptophans. The synthesis of Fmoc-dehydrobutyrine 1.55 and Fmoc-dehydrophenylalanine 1.56 were achieved through a pyridine mediated β-elimination of tosylated Fmoc-threonine and Fmoc-hydroxyphenylalanine, respectively. This thesis also reported a successful installation of four β-substituted Fmoc-dehydroamino acids, Fmoc-dehydrobutyrine 1.55, Fmoc-dehydrophenylalanine 1.56, Fmoc-dehydrovaline 4.24 and Fmoc-dehydroleucine 4.25, during Fmoc/tBu solid-phase peptide synthesis for the replacement of dehydroalanine in argyrin.

The 4-Br-L-tryptophan dehydrobutyrine containing argyrin 4.42 was identified to have the most potent in vitro activity against P. aeruginosa and B. multivorans. Most importantly, the replacement of dehydroalanine residue with dehydrobutyrine improved the antibacterial activity of argyrin towards P. aeruginosa and B. multivorans. This finding indicates that dehydroamino acid not only control the planarity of the cyclic structure of argyrin but also play an important role in the interaction between argyrin and EF-G.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Chan, Weng
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 49610
Depositing User: Yang, Lei
Date Deposited: 27 Sep 2021 11:56
Last Modified: 27 Sep 2021 11:57

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