The effects of 6-benzyl-1,3-benzodioxole derivatives on the alkylation of tubulin.

Derivatives of 6-benzyl-1,3-benzodioxole are known to bind to tubulin and inhibit tubulin polymerization. For a better understanding of the mechanism of action of the 6-benzyl-1,3-benzodioxole derivatives, we have examined their effect on the alkylation of tubulin sulfhydryls by iodo[14C]acetamide and N,N'-ethylene(bis)iodoacetamide. We have found that the 6-benzyl-1,3-benzodioxole derivatives with an intact dioxole ring affect alkylation to an extent proportional to their ability to inhibit tubulin polymerization. Those derivatives with the strongest resemblance to podophyllotoxin have the weakest effects. However, derivatives with a disrupted dioxole ring show little or no ability to inhibit polymerization, but their effect on alkylation is directly related to the degree of resemblance they bear to the trimethoxy ring of podophyllotoxin. It thus appears that the relatively simple approach of using alkylating agents can generate a significant amount of information on the mechanism by which various drugs interact with tubulin.