Antineoplastic agents 360. Synthesis and cancer cell growth inhibitory studies of dolastatin 15 structural modifications

Dolastatin 15 (1), a potent antineoplastic constituent of the Indian Ocean shell-less mollusk Dolabella auricularia, was utilized as the lead substance for a series of structure-activity studies. The synthetic methods, in vitro evaluations against a variety of murine and human cancer cell lines, as well as a selection of bacteria and fungi, and inhibition of tubulin polymerization are described. Remarkably, all of the compounds studied, in which the C-terminal (S)-dolapyrrolidinone unit (Dpy) was replaced with a series of structurally diverse and more readily available amides, showed cancer cell growth inhibition activities generally quite comparable to those of the parent molecule (1). All analogues, however, were less potent than 1 as inhibitors of tubulin polymerization. The structurally modified peptides, like the parent compound, caused mitotic arrest in cultured cells, consistent with tubulin being the primary cellular target. The ability of dolastatin 15 and eight modifications or precursors thereof to inhibit the growth of a Gram-negative bacterium suggests that these compounds have an additional target distinct from tubulin.