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 (IC(5)(0) 1.4 +/- 1.3 muM) and S1 (IC(5)(0) 1.8 +/- 0.9 muM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC(5)(0) 15.8+/-3.7 muM; 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 muM 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 IC(5)(0) values <10 muM. 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 muM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and beta-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.
Balaji, N. V., et al. (2015). “Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs.” Bioorg Med Chem 23(9): 2148-2158.