Isomerization of antitumour bicyclic hexapeptide, RA-VII from Rubia Cordifolia. Part 4. Conformation–antitumour activity relationship

Abstract

A bicyclic hexapeptide, RA-VII, isolated from Rubia cordifolia, has been isomerized under basic conditions to give four derivatives (compounds 1–4). In compounds 1 and 2, both Tyr-5 and -3 residues were isomerized to give an energetically more favourable alternate D and L amino acid peptide sequence and in compounds 3 and 4, a Tyr-5 residue was isomerized. Conformational analyses of compounds 1–4 in solid and solution states were conducted by X-ray and NMR analysis. The N-methyl amide bond between D-Tyr-5 and Tyr-6 is trans in compounds 1–4. The geometry of the amide bond on the turn at residues 2 and 3, which is considered to play an important role in the antitumour activity, was found to be trans in compounds 1 and 2, and cis in compounds 3 and 4. Compounds 3 and 4 shows antitumour activities. The conformation of the cis N-methyl amide bond between residues 2 and 3 is shown to play an important role in the antitumour activities of RAs.