AXINASTATIN 1 OR MALAYSIATIN - PROOF OF CONSTITUTION AND 3D STRUCTUREIN SOLUTION OF A CYCLIC HEPTAPEPTIDE WITH CYTOSTATIC PROPERTIES

Recently, a cyclic heptapeptide with cytostatic activity was isolated from marine sources by three different groups independently. The seque nce of the isolated peptide was ambiguous, since two different isomers have been proposed: Asn(1)-Pro(2)-Phe(3)-Val(4)-Val(5)-Pro(6)-Val(7)- ) (1) also called axinastatin 1 resp. pseudooxinellin and -Pro(2#)-Pro (3#)-Phe(4#)-Val(5#)-Val(6#)-Val(7#)-) (2) called malaysiatin. We synt hesized both peptides 1 and 2 and compared their optical rotation, FAB -MS, H-1- and C-13-NMR data with those of the native compounds. Our re sults prove that peptide 1 has been assigned correctly, whereas the da ta of 2 differ significantly from those of the natural peptide. Peptid e 1 adopts two conformations (90:10 ratio) in DMSO, interconverting sl owly on the NMR time scale. According to MD simulations, using NOEs an d J couplings as experimental restraints, a beta VIa-turn with a cis p eptide bond between Val(5)-Pro(6) and a beta I-turn in the Asn(1)-Val( 4) region are the characteristic secondary structural elements of the major conformer. Its backbone conformation is very similar to the X-ra y structure of a related peptide Asn(a)-Leu(b)-Ser(c)-Phe(d)-Leu(e)-Pr o(f)-Val(g)-) called evolidine.