Background: The heptaprotective flavonolignan silibinin and dehydrosilibinin have exhibited
moderate antiproliferative activities toward many cancer cell lines. Considering of the nontoxic profile of these
natural products, chemical modification to enhance the anticancer potentials is promising.
Method: A series of 7-O-aminoalkyl-2,3-dehydrosilibinin derivatives were synthesized and evaluated for their
antiproliferative activities against several cancer cell lines.
Results: A number of the synthesized dehydrosilibinin derivatives exhibited greatly enhanced potency with 50%
growth inhibition at low micromolar concentrations. Structure activity study indicated that the distance between
N and 7-O on the side chain has a limited influence on the antiproliferative activity, while the presence of a
morpholino group decreases the antiproliferative activities dramatically. Flow cytometry based assays on human
colon cancer HCT116 cells revealed that 6a and 6c, two of the most potent derivatives, effectively arrested the
cell cycle in the G2 phase and stimulated cell apoptosis.
Conclusion: Our findings suggest that attaching an appropriate tertiary amino alkyl side chain through 7-Oalkylation
on 2,3-dehydrosilibinin, would be a viable strategy for the development of silibinin derivatives as