Three epimers of a natural cyclic hexapeptide
RA-VII were prepared via formation of
oxazoles from
thioamides or thioimidates of
RA-VII followed by hydrolysis. They are the epimers at l-Ala-1, d-Ala-2, and d-Ala-4, respectively. The one having l-Ala-1 adopted trans-cis-trans-trans-trans-trans (t-c-t-t-t-t)
amide configurations in the crystal, a type-VI beta-turn for residues 1-4 stabilized by one intramolecular hydrogen bond between Ala-4 NH and l-Ala-1 C = O, and in CDCl(3) existed as a mixture of six conformers, of which the major conformer was very similar to that in the crystal, but quite different from that of
RA-VII in
solution. The second epimer, having d-Ala-2 had in the crystalline state t-t-t-t-c-t
amide configurations, a gamma-turn at Tyr-3 stabilized by two intramolecular hydrogen bonds between d-Ala-2 NH and Ala-4 C = O and between Ala-4 NH and d-Ala-2 C = O, and existed in CDCl(3) as a single conformer, the structure of which was very similar to its crystal structure, and to the crystal structure of
peptide 25 except for the backbone and the side chains at residues 1 and 2. The third epimer, having d-Ala-4 had t-c-t-t-c-t
amide configurations in the crystal, a type-VI beta-turn for residues 1-4 as observed in the first epimer, and in CDCl(3) existed in three conformers, of which the major one was similar to that in the crystal but different from that of
RA-VII in
solution. The three epimers showed very weak cytotoxicity on P-388
leukemia cells, which may be because of their conformational differences from the active conformation of
RA-VII.