Thiazole containing macrocyclic peptides

Sokolenko, Nikolai. (2001). Thiazole containing macrocyclic peptides MPhil Thesis, School of Molecular and Microbial Sciences, The University of Queensland.

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Author Sokolenko, Nikolai.
Thesis Title Thiazole containing macrocyclic peptides
School, Centre or Institute School of Molecular and Microbial Sciences
Institution The University of Queensland
Publication date 2001
Thesis type MPhil Thesis
Total pages 153
Collection year 2001
Language eng
Subjects L
250204 Bioinorganic Chemistry
780105 Biological sciences
Formatted abstract
Ascidians are a class of marine organisms which produce a large number of biologically active organic compounds. Macrocyclic peptides isolated from ascidians have been found to contain oxazoline and thiazole subunits in their structures. These heterocyclic rings are synthesised by side chain to backbone cyclisations of the amino acids Thr, Ser or Cys and can fix localised conformation in a cyclic peptide. These cyclic peptides coordinate metal ions within their macrocyclic cavity and also co-crystallise with benzene, ethanol or water trapped inside the cyclic peptide cavity.

Chapter 2 describes the synthesis of two cyclic octapeptides cyclo-[-Ile(Oxn)-DVal( Thz)-]₂ and cyclo-[-Ile(Oxn)-D-Phe(Thz)-]₂ which are analogues of ascidiacyclamide, a cyclic octapeptide isolated from ascidians. This involved a modified Hantzsch thiazole synthesis, construction of the peptide chains, followed by cyclisation, and then formation of oxazoline rings using Burgess reagent. Both molecules are C₂ symmetric and their three dimensional structure should therefore be similar to that of ascidiacyclamide.

Chapter 3 describes a one pot cyclo-oligomerisation of the linear tripeptide analogues H-Ser-D-Val(Thz)-OH, H-Ser-D-Phe(Thz)-OH and the tetrapeptide analogue H-Ile-Ser-DVal( Thz)-OH which leads to a novel series of constrained macrocyclic peptides cyclo-[-Ser-DVal( Thz)-]n, cyclo-[-Ser-D-Phe(Thz)-]n, n = 2-6; and cyclo-[Ile-Ser-D-Val(Thz)-]n, n = 2-19. The macrocycles cyclo-[-Ile-Ser-D-Val(Thz)-]n, n = 2-10, have been isolated and fully characterised. The high symmetry (Cn) of the macrocycles, which contain up to 76 amino acids, appears to confer some limited mobility of individual planar regions formed by thiazoles conjugated to amide bonds. The turn-favouring properties of the D-Val(Thz) component are responsible for encouraging cyclo-oligomerisation. This approach to unusually large macrocycles may be used in combinatorial syntheses to generate libraries of novel functionalised macrocycles.

A large number of compounds with supramolecular structures has been described in the scientific literature, however, very few of them were based on natural products. In Chapter 4 it was considered that rigid cyclic hexapeptides with thiazole could be possible scaffolds for construction of cone and cylinder-shaped molecules. Cyclo-oligomerisation of a thiazole containing dipeptide derivative H-D-Val(Thz)-OH gave the corresponding cyclic hexapeptide [- D-Val(Thz)-]₃ and octapeptide [-D-Val(Thz)-]₄. Using the same method, functionalised thiazole-containing dipeptides H-Glu(OtBu)(Thz)-OH and H-Lys(Z)(Thz)-OH were cyclo-oligomerised to cyclic hexapeptide analogues, cyclo-[-Glu(OtBu)(Thz)-]₃ and cyclo-[- Lys(Z)(Thz)-]₃ respectively. These functionalised macrocycles were then coupled to one another via three deprotected Glu and three deprotected Lys side chains producing a highly constrained cylindrical peptide. Alternatively cycIo-[-GIu(OtBu)(Thz)-]₃ was converted to a cone-shaped peptide by condensing the three Glu side chains (as the reduced bromide analogue) with 1,4,7-triazacyclononane. These novel and highly symmetrical cone- and cylinder-shaped peptides may present new opportunities to study interactions between small molecules and peptides, and could potentially be elaborated to catalysts and artificial proteins.

Keyword Macrocyclic compounds
Macrocyclic compounds -- Synthesis

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Fri, 24 Aug 2007, 17:48:22 EST