Antitubulin activities of ansamitocins and maytansinoids

Antitubulin activities of ansamitocins, maytansine and four maytansinoids which are structurally related to ansamitocins were studied using three reaction systems; inhibition of polymerization of bovine brain tubulin, depolymerization of the once polymerized tubulin, and immunofluorescent staining of cytoplasmic microtubules in A31 cells. Ansamitocin P-3, ansamitocin P-4, maytansine, D-maytansine, maytanacine and maytansinol 3-propionate inhibited the polymerization of tubulin and depolymerized the once polymerized tubulin. The concentrations of these compounds causing 50 per cent inhibition of polymerization and 50 per cent depolymerization were around 3.4 and 3.8 x 10(-6) M, respectively. Maytansinol also inhibited polymerization of tubulin and depolymerized the once polymerized tubulin. However, maytansinol was about four times less effective in polymerization inhibition and ten times less effective in depolymerization than other compounds. Except for maytansinol and D-maytansine, these compounds caused a disappearance of fibers of cytoplasmic microtubules in A31 cells at a concentration of 1-6 x10(-8) M. The concentration of D-maytansine causing the disappearance of the fibers was about 50 times higher than that of maytansine. Maytansinol did not cause the disappearance of the fibers even at such a high concentration as 4.6 x 10(-6) M. These results suggest that the ester moiety at the C-3 position of ansamitocins, maytansine and maytansinoids plays an important role in increasing their permeation into living cells.