Synthesis and cytotoxicity evaluation of retro-inverso analogue of antitumor bicyclic hexapeptide RA-VII

Abstract

A retro-inverso analogue of antitumor bicyclic hexapeptide RA-VII was designed and synthesized. A cycloisodityrosine unit was synthesized by the intramolecular diphenyl ether formation of Boc-3-borono-d-Tyr(Me)-d-Tyr-OMe mediated by copper(II) acetate and 4-(dimethylamino)pyridine. After the N-methylation, Boc-Ala-OH and the tripeptide segment were sequentially coupled to the N-terminus of the cycloisodityrosine unit, affording a hexapeptide. After removal of the C- and N-terminal protecting groups, the hexapeptide was subjected to macrocyclization using diphenylphosphoryl azide and NaHCO3 in N,N-dimethylformamide to afford a bicyclic hexapeptide analogue. X-ray crystallography and NMR experiments showed that the analogue had different structural features from RA-VII, which were responsible for the lack of cytotoxic activity of the analogue.