Design and synthesis of analogues of RA-VII—an antitumor bicyclic hexapeptide from Rubiae radix

The 14-membered cycloisodityrosine is the core structure of RA-series antitumor bicyclic peptides obtained from Rubia plants (Rubiaceae). In this study, an efficient method for the synthesis of cycloisodityrosines from commercially available l-tyrosine derivatives was developed. Using synthetic cycloisodityrosines and cycloisodityrosines with modified structures, several RA-VII analogues were designed and synthesized to explore structure–activity relationships of the cycloisodityrosine moiety of the RA-series peptides, and newly isolated natural peptides were synthesized to establish their structures. Graphic abstract