The conformation of cyclo[l-pro-l-leu-l-val-(gly)thz-(gly)thz], a dolastatin 3 analog, in the crystalline and solution states

Abstract

Cyclo[L-Pro-L-Leu-L-Val-(gly)Thz-(gly)Thz], (1), has been prepared in high yield using pentafluorophenol in the ring closure reaction. This dolastatin 3 analog has been subjected to crystal structure analysis (space-group P6 5, a = b = 34.897(9), c = 24.611(10)Å, asymmetric unit contents:(C 26H 35N 7O 5S 2)4·(C 7H 8)7·(CH 30H) 4, ϱ calc = 1.202gcm-3.) and solution (CDCl 3 and DMSO-d 6) studies using 1H- and 13C-NMR techniques. The molecule has been found to adopt a clearly preferred conformation both in the crystal and in solution. The conformation contains a cis (gly)Thz-Pro peptide bond and two intramolecular hydrogen bonds, one from Leu-NH to a thiazole endocyclic nitrogen atom and the other from a (gly)Thz-NH to the Leu-C=O. The results of this study not only demonstrate that the conformation of (1) is very similar in the crystal and solution, but also provide conclusive evidence that the conformation proposed by Bernier, et al 4. earlier is incorrect. The crystal packing demonstrates that (1) is a very hydrophobic cyclopeptide with a tendency to self associate. In the crystal (1) associates via systematic hydrogen bonding to form a network of interlocking hydrophobic tubes filled with toluene molecules. The solvent molecules migrate out of the crystals on exposure to air resulting in fragmentation.