CONFORMATIONAL-ANALYSIS OF ANTITUMOR CYCLIC HEXAPEPTIDES, RA SERIES

Conformational analysis of an antitumor cyclic hexapeptide, RA and its analogues isolated from Rubia akane and R.cordifolia was conducted by the spectroscopic and computational chemical methods. A combination of different homo- and heteronuclear two-dimentional NMR techniques at 500MHz have enabled us to perform complete assignment of the H-1 and C-13 signals of the two conformers A and B of RA-VII in CDCl3. The structures of the three conformers (A, B and C) in DMSO-d6 were also determined by 2D-NMR techniques, temperature effects on NH protons and NOE experiments. Distances deduced from the NMR measurements were used for the refinements by the restrained molecular dynamics calculations using AMBER program. These conformational analysis showed that these conformers were caused by geometrical isomerization and that the predominant conformer A exhibits a typical type II beta-turn structure, which is similar to the crystal structure analyzed by the X-ray diffractions. The reduced biological activity of the N-methyl derivative of RA-VII in comparison to RA-VII may be responsible for the more weakly populated conformer A in solution. Further, the presence of a highly strained 14-membered ring was necessary to maintain the typical type II beta-turn structure of conformer A, and the ring system and turn structure were considered to play an important role in its antitumor activity.