On-Resin Synthesis and Pharmacokinetic Evaluation of the Oxazole-Containing Peptide: Wewakazole B

Abstract

Peptides have long been utilized as therapeutic agents for treating cancer, enzyme deficiency disorders, and infectious diseases due to their low toxicity, high selectivity, and specificity. Wewakazole B, a cyanobactin, was first isolated from the cyanobacterium, Moorea producens, collected in the Red Sea by Lopez et al. Comprising nine common and three modified amino acid residues, Wewakazole B has demonstrated cytotoxicity against human H460 lung cancer and MCF7 breast cancer cells. Although several research groups have achieved the total synthesis of Wewakazole B using classical solution phase peptide synthesis (CSPS), this method is time-consuming, tedious, and low yielding. This thesis details our efforts to synthesize Wewakazole B and the first-generation structural analogues using solid phase peptide synthesis (SPPS). The pharmacokinetic properties, lipophilicity and human serum stability, of the synthesized peptides were evaluated to assess their potential as drug candidates. All peptides exhibited good lipophilicity and demonstrated stability in 25% human serum. Additionally, the thesis examines the on-resin synthesis of oxazoles and methyloxazoles, aiming to apply these methods to the total on-resin synthesis of Wewakazole B.