Abstract:
This thesis describes the synthesis of peptidomimetics for use as potential therapeutic agents for the treatment of cancer metastasis and inflammation-related diseases. This study focuses on the preparation of a library of analogues based on the cyclic hexapeptide lead, c(RLhSβKDK) 23 identified by Bartsch and Koller.1 A structure-activity relationship study was conducted on these peptidomimetics to investigate the effect of structural modifications on their abilities to inhibit homophilic and heterophilic interactions of ADAM8 implied in disease states. The peptidomimetics were prepared in two steps: a) First, Fmoc SPPS was used to synthesise the linear precursor outlined in Scheme 1; b) followed by in-solution head-to-tail macrocyclisation was employed to afford the desired product (Scheme 13). Compounds 24-41 were synthesised by systematically substituting natural amino acid residues for non-proteinogenic analogues during SPPS. These analogues were assessed for their ability to inhibit ADAM8 sheddase activity of which the analogues that performed the best were tested for their stability; both were performed in vitro. The hydroxymethyl group of the -homoserine group is crucial for inhibiting ADAM8 demonstrated by the drop of activity upon its substitution for other functional groups. Substitutions for arginine and leucine were also explored. Hydrogen bonding from a guanidine group has shown importance for the arginine position. On the other hand, increased hydrophobicity seems to have improved the activity of the peptide as demonstrated by peptide 32. Unfortunately, peptide 32 has demonstrated poor stability when compared to the lead peptide 23. This study provides valuable insight into the structural requirements influencing the interaction between the peptide and its receptor and provides solid ground for the development of potent therapeutics against metastatic cancer and inflammation-related diseases.