Anticancer properties of 2-piperidyl analogues of the natural indole phytoalexin 1-methoxyspirobrassinol.
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 NCI(60) panel of human cancer cells. The COMPARE program was employed to analyze patterns of activity of compounds 4-7 against the NCI(60) 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 NCI(60) panel and, consistent with COMPARE prediction, a glutathione-depleting effect on MCF-7 cells.


CONCLUSIONS
Considering their remarkable glutathione-depleting effects, compounds 4-7 could be developed as radio- and/or chemosensitizing agents for combination cancer chemotherapy.
Mezencev
Roman
R
Georgia Institute of Technology, School of Biology, Atlanta, GA 30332, USA. rmezencev3@gatech.edu
Kutschy
Peter
P
Salayová
Aneta
A
Curillová
Zuzana
Z
Mojzis
Ján
J
Pilátová
Martina
M
McDonald
John
J