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 O cean shell-less mollusk Dolabella auricularia, was utilized as the lea d substance for a series of structure-activity studies. The synthetic methods, in vitro evaluations against a variety of murine and human ca ncer cell lines, as well as a selection of bacteria and fungi, and inh ibition of tubulin polymerization are described. Remarkably, all of th e compounds studied, in which the C-terminal (S)-dolapyrrolidinone uni t (Dpy) was replaced with a series of structurally diverse and more re adily available amides, showed cancer cell growth inhibition activitie s generally quite comparable to those of the parent molecule (1). All analogues, however, were less potent than 1 as inhibitors of tubulin p olymerization. The structurally modified peptides, like the parent com pound, caused mitotic arrest in cultured cells, consistent with tubuli n being the primary cellular target. The ability of dolastatin 15 and eight modifications or precursors thereof to inhibit the growth of a G ram-negative bacterium suggests that these compounds have an additiona l target distinct from tubulin.