Crystal and molecular structure of didemnin A, an antiviral depsipeptide

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Abstract
The molecular structure of didemnin A, the parent compound of a series of antiviral cytotoxic depsipeptides extracted from a marine tunicate Trididemnum solidum of the family of Didemnidae, has been determined by single-crystal X-ray diffraction. In the crystal, didemnin A molecules form pseudo-symmetric dimeric pair. The two molecules in the dimer are held together by strong N—H…O and N—H…N hydrogen bonds. A chloride ion, placed almost symmetrically between the dimeric pair, forms N—H…Cl hydrogen bonds (3.19 and 3.23 Å) with both the molecules. The two independent molecules in the structure have closely similar geometry. For each molecule, the 23-membered depsipeptide ring assumes a folded conformation in the shape of a ‘bent figure-of-eight’ similar to that observed in the didemnin B crystal structure. The major conforma-tional differences in the macrocycle of didemnin A and didemnin B are around the Hip residue. The root mean-square (RMS) difference of 20 of the 23 endocyclic torsion angles for the two structures is less than 10°, while the three bond torsions in the Hip residue vary by about 50°. The macrocycle conformation is stabilized by a transannular N—H…O hydrogen bond linking the isostatine amide group with the leucine carbonyl group. The truncated linear chain is folded back toward the macrocyclic ring and is held by a N—H…O hydrogen bond between the leucine amide group and Me-Leu carbonyl group. The transannular hydrogen bond in the didemnin A structure (N4—H…O3 = 2.83 Å in both molecule a and molecule b) is noticeably stronger than that observed in the didemnin B structure (3.02 Å). The X-ray structure of didemnin A is generally consistent with that obtained by NMR studies. Within the crystal, the molecules are packed in zig-zag chains formed by intermolecular O— H…O hydrogen bonds. The crystal structure and packing of didemnin A are quite different from that of the dideninin B structure. © Munksgaard 1996.