Synthesis and molecular modeling study of dolastatin 11 analogues

Abstract

Nine analogues of dolastatin 11, a potent antineoplastic agent from an Indian Ocean sea hare which interferes with microfilaments, were synthesized, including two natural ones. Although none of these analogues showed stronger activity than dolastatin 11, their syntheses gave better understanding of the structure-activity relationships for dolastatin 11 as described below. The complete lack of activity of the hydroxy acid obtained by hydrolysis of dolastatin 11 showed that the 30-membered ring may be necessary for activity. The high activity of the 3- and 7-nor derivatives showed that the 3- and 7-methyl groups are not needed for strong activity; the former is a drug candidate since it can be prepared pure more economically than dolastatin 11. The synthesis of Ala-epi-dolastatin 11 showed that this stereoisomer has greatly decreased activity, and that it is the persistent by-product in the dolastatin 11 synthesis. Molecular modeling studies showed most of these analogues to have conformations very sin-filar to those of dolastatin 11. However, the very weak activities of the two conformationally-restricted analogues synthesized suggests that none of the three lowest-energy conformations of dolastatin 11 is the binding conformation to F-actin. Two natural analogues isolated from Pacific Ocean blue-green algae were synthesized. The synthesis of the very active majusculamide C confirmed its structure, but the synthesis of the much less active lyngbyastatin 1 showed its configuration in the Ibu unit to have been assigned incorrectly, and that Ibu-epi-dolastatin 12 is a natural product which accompanies it. The broadness of the peaks in the NMR spectra of these two natural products was shown to be due to rotation about their Ibu-Ala amide bonds.