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Background: Several indole phytoalexins exhibit antiproliferative and/or cancer chemopreventive properties in vitro. However, the potency and selectivity of their anticancer effects were reported to be relatively weak. In order to improve the anticancer activity of the natural phytoalexin 1-methoxyspirobrassinol, its new 2-amino analogues were synthesized and evaluated. Methods:Cis-1-Boc-, trans-1-Boc-, cis-1-methoxy- and trans-1-methoxy-2-deoxy-2-(1-piperidyl)spirobrassinols (compounds 4–7) were synthesized by spirocyclization reaction and their potency evaluated by SRB assay on the NCI₆₀ panel of human cancer cells. The COMPARE program was employed to analyze patterns of activity of compounds 4–7 against the NCI₆₀ panel for prediction of their probable targets and mode of action. Cellular glutathione, a predicted target, was quantified by DTNB assay. Results: Compounds 4–7 exhibit growth inhibitory effects across the NCI₆₀ panel and, consistent with COMPARE prediction, a glutathione-depleting effect on MCF-7 cells. Conclusion: Considering their remarkable glutathione-depleting effects, compounds 4–7 could be developed as radio- and/or chemosensitizing agents for combination cancer chemotherapy.