Design, Synthesis, and Antitumor Activity Study of All-Hydrocarbon-Stapled B1-Leu Peptides

B1-Leu peptide is a structural optimization compound derived from the lysine- and phenylalanine-rich antimicrobial peptide Cathelicidin-BF. It has shown promising antibacterial and antitumor biological activity. However, linear peptides are not the best choice for novel drug development due to their poor pharmacokinetic properties. In this study, various all-hydrocarbon stapled B1-Leu derivatives were designed and synthesized. Their secondary structure, protease stability, and antitumor and hemolytic activities were also investigated to evaluate their clinical value for cancer therapy. Among them, B1-L-3 and B1-L-6 showed both damaging the tumor cell membrane stability and antitumor activity, showing that they are promising lead compounds for the development of novel cancer therapeutics.