Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage.
Brassinin [3-(S-methyldithiocarbamoyl)aminomethyl indole], a phytoalexin first identified as a constituent of cabbage, was synthesized and evaluated for cancer chemopreventive activity. Dose-dependent inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced preneoplastic lesion formation was observed with mouse mammary glands in organ culture, as was dose-dependent inhibition of DMBA-induced mouse skin tumors that were promoted by treatment with 12-O-tetradecanoylphorbol-13-acetate. Cyclobrassinin is a biologically derived product of the oxidative cyclization of brassinin, and was as active as the parent compound in inhibiting the formation of preneoplastic mammary lesions in culture; however, 2-methylbrassinin was not significantly active in this process. Therefore, oxidative cyclization may be an effective metabolic activation step. As judged by these tumor inhibition studies in conjunction with potential to induce phase II enzymes in mice or cell culture, brassinin may be effective as a chemopreventive agent during both the initiation and promotion phases of carcinogenesis. This is the first report documenting the chemopreventive potential of structurally novel indole-based phytoalexins that are naturally occurring in cruciferous vegetables, and the synthetic route described herein has proven amenable for scale-up production. The bifunctional structural nature of brassinin, bearing both an indole nucleus and a dithiocarbamoyl-aminomethyl moiety, is notably similar to the individual structural elements of other known chemopreventive agents such as indole-3-carbinol or benzylisothiocyanate. The favorable biological activity demonstrated by the compound may originate from the presence of these two moieties.
Specialized Cancer Center, College of Medicine, University of Illinois at Chicago 60612.
R G
RG
Mehta
J
J
Liu
A
A
Constantinou
C F
CF
Thomas
M
M
Hawthorne
M
M
You
C
C
Gerhüser
J M
JM
Pezzuto
R C
RC
Moon
R M
RM
Moriarty
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D005260:Female; D007211:Indoles / Q000138:chemical synthesis* / Q000627:therapeutic use*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D012878:Skin Neoplasms / Q000517:prevention & control*; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000627:therapeutic use*; D000094162:Phytoalexins
D015127:9,10-Dimethyl-1,2-benzanthracene; D016588:Anticarcinogenic Agents; D007211:Indoles; D013859:Thiocarbamates; C089020:brassinin; D000094162:Phytoalexins