Aza-cycloisodityrosine analogue of RA-VII, an antitumor bicyclic hexapeptide

An aza-cycloisodityrosine analogue of RA-VII, 3, was designed and synthesized. The key aza-cycloisodityrosine unit was prepared by copper(II)-acetate-mediated intramolecular phenylamine/arylboronic acid coupling of dipeptide followed by connection with the tetrapeptide segment to afford a hexapeptide. Subsequent macrocyclization of the hexapeptide with EDC·HCl and HOOBt under dilute conditions gave 3. Analogue 3 showed significant cytotoxic activity against human promyelocytic leukemia HL-60 cells and human colon carcinoma HCT-116 cells, but its activity was weaker than that of parent peptide RA-VII (1).