CANCER CHEMOPREVENTIVE ACTIVITY OF BRASSININ, A PHYTOALEXIN FROM CABBAGE

Brassinin [3-(S-methyldithiocarbamoyl) aminomethyl indole], a phytoale xin first identified as a constituent of cabbage, was synthesized and evaluated for cancer chemopreventive activity. Dose-dependent inhibiti on of 7,12-dimethylbenz[a]anthracene (DMBA)-induced preneoplastic lesi on formation was observed with mouse mammary glands in organ culture, as was dose-dependent inhibition of DMBA-induced mouse skin tumors tha t were promoted by treatment with 12-O-tetradecanoylphorbol-13-acetate . Cyclobrassinin is a biologically derived product of the oxidative cy clization of brassinin, and was as active as the parent compound in in hibiting the formation of preneoplastic mammary lesions in culture; ho wever, 2-methylbrassinin was not significantly active in this process. Therefore, oxidative cyclization may be an effective metabolic activa tion step. As judged by these tumor inhibition studies in conjunction with potential to induce phase II enzymes in mice or cell culture, bra ssinin may be effective as a chemopreventive agent during both the ini tiation and promotion phases of carcinogenesis. This is the first repo rt documenting the chemopreventive potential of structurally novel ind ole-based phytoalexins that are naturally occurring in cruciferous veg etables, and the synthetic route described herein has proven amenable for scale-up production. The bifunctional structural nature of brassin in, bearing both an indole nucleus and a dithiocarbamoylaminomethyl mo iety, is notably similar to the individual structural elements of othe r known chemopreventive agents such as indole-3-carbinol or benzylisot hiocyanate. The favorable biological activity demonstrated by the comp ound may originate from the presence of these two moieties.