Modified Solid Phase Peptide Synthesis of Polymyxin E1 Antibiotic Analogues Using Microwave Assisted Irradiation

Abstract

In the present thesis five analogues of Polymyxin E1 antibiotic were synthesized via Fmoc-modified solid phase peptide synthesis (SPPS) strategy using Biotage® Initiator+Alstra™ microwave peptide synthesizer. Among all the research studies discussing the synthesis of various analogues of polymyxin antibiotics, this work represents the first one focusing on the replacement of five toxic Dab residues in both the cyclic heptapeptide moiety and the tripeptide tail of Polymyxin E1, with a natural amino acid, Arg. The only Dab4 residue involved in lactam cyclization was substituted with another natural amino acid, Lys. Additionally modifications of the tripeptide tail part have been introduced into two analogues. These compounds were cyclized using different techniques, either side-chain to C-terminal in solution via L-Lys4, L-Thr10, in analogues (I-III) or side-chain to side-chain cyclization on polymeric support via L-Lys4, L-Asp10 in analogues (IV &V) to investigate the influences of different cyclization conditions on the purity and yield of the final products. On polymeric support cyclization has emerged as a powerful approach for the synthesis of cyclopeptidomimetics, which perform the cyclization reaction while the linear peptide is still anchored on the resin.