Synthesis and cytotoxicity evaluation of tyrosine-3 or tyrosine-6 fluorinated analogues of RA-VII, an antitumor bicyclic hexapeptide from Rubia cordifolia

Abstract

An RA-VII analogue with a fluorine atom introduced to the Tyr-3 ε position was synthesized from cycloisodityrosine, obtained through the chemical degradation of RA-VII, and fluorotetrapeptide. Additionally, an analogue with a fluorine atom at the Tyr-6 εa position was prepared via a substitution reaction involving the amino group of an amino-RA-VII derivative using a fluoride species. Compared with RA-VII, the Tyr-3 fluorinated analogue exhibited 300 times lower cytotoxicity toward the HL-60 cell line and 370 times lower cytotoxicity toward the HCT-116 cell line. In contrast, the Tyr-6 fluorinated analogue was 3.3 times and 1.1 times less cytotoxic toward these cell lines than RA-VII. These results indicate that substituting a fluorine atom for the aryl proton at the Tyr-3 ε position markedly reduces the cytotoxic activity. In contrast, the impact of such substitution at the Tyr-6 εa position is minimal.