AbstractChitin, a linear polymer of N-acetylglucosamine, is an essential structural component of fungal, nematode and insect pathogens but is not found in human physiology. Chitinases, which hydrolyze this polymer, play a key role in life cycle of these pathogens and associated pathogenesis. Consequently chitinase inhibitors have generated a lot of interest given their potential as insectides, fungicides and antimalarials.Herein, approaches are reported to the synthesis of some non-sugar based chitinase inhibitors: the cyclic pentapeptide natural products argifin, banyasin A and diketopiperazines related to the natural product CI-4. In order to improve the efficiency of production of argifin and facilitate SAR on analogues of the natural product, a revised synthesis of argifin has been developed.The synthesis of argifin was carried out by a combination of solid-phase and solution chemistry. The assembly of the linear peptide was carried out by SPPS and the cyclisation was performed in solution. The protecting groups chosen for the Asp and Arg residues were removable by hydrogenolysis, as this allowed aspartimide formation under acidic conditions to be avoided. Only one HPLC purification was required at the final step; argifin was isolated in 19% yield, compared to 18% yield for the first synthesis by Dixon et al.Banyasin A contains the same essential Arg(MC)-MePhe dipeptide motif as argifin and so it is of considerable interest as a potential Family 18 chitinase inhibitor. The synthesis of Amoa (3-amino-2-methyl-5E-octenoic acid) a rare amino-acid present in banyasin A was investigated. An advanced intermediate for the synthesis of Amoa was successfully obtained via chiral pool chemistry in an 8 step sequence from L-Asp. This involved preparation of a selectively protected β-methyl-substituted Asp derivative, which was then homologated to the β-amino-acid via Arndt-Eistert chemistry to give (3R,4R)-3-(((benzyloxy)carbonyl)amino)-4-methyl-5-oxo-5-allyloxypentanoic acid in 27% yield for the final step.The cyclic dipeptide CI-4, cyclo (L-Arg-D-Pro) is a weak inhibitor (IC50 = 1.2 mM) of Family 18 chitinases, however its binding efficiency index (BEI) is comparable to more potent inhibitors such as argifin. Some analogues of CI-4 show promising activity against a typical bacterial type Family 18 chitinase, SmChiB1 from Serratia marcescens. The cyclic dipeptide should therefore be a useful starting point for the development of more effective and selective inhibitors of this enzyme class. A series of cyclo (Xaa-Pro)-based dipeptides were synthesized, with different Xaa such as L/D-Pro, Gly, L-Ser, L/D-Arg, D-His, D-Phe, with yields ranging from 12 to 84%. Preliminary biological data confirm that cyclo(D-Xaa-D-Pro) may be a novel template for the development of new drug-like inhibitors of Family 18 chitinases.
|Date of Award||2 Nov 2015|
|Supervisor||Ian Eggleston (Supervisor)|
Synthesis of cyclic peptide natural products and peptidomimetics
Bunga, F. (Author). 2 Nov 2015
Student thesis: Doctoral Thesis › PhD