Phytochemicals play an important role in
cancer therapy.
Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human
cancer cell lines using the in vitro cell-based MTT assay. Among the
hispolon analogs tested, compound
VA-2, the most potent overall, produced its most significant effect in the
colon cancer cell lines HCT-116 (IC₅₀ 1.4 ± 1.3 μM) and S1 (IC₅₀ 1.8 ± 0.9 μM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC₅₀ 15.8±3.7 μM; p<0.01 for each comparison). Based on our results,
VA-2 was about 9- to 11-times more potent in
colon cancer cells and 2- to 3-times more potent in
prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of
VA-2 showed significant reduction of cell number, while the cells' sizes were also markedly increased and were obvious at 68 h of treatment with 1 μM in HCT-116 (colon) and PC-3 (
prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of
hispolon, inhibited prostate and
colon cancer cell lines with IC₅₀ values <10 μM. In addition,
hispolon isoxazole and
pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean ICv values in the range 3.3-10.7 μM in all the
cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and β-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-
cancer drugs, suggesting they may be more effective
anticancer agents.