Abstract
Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and β′-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioactivities, including antioxidant, anti-inflammatory, anti-proliferation and anticancer activity. A series of novel curcuminoid derivatives (a total of 55 new compounds) and three reference compounds were synthesized with good yields using three-step organic synthesis. The anti-proliferative activities of curcumin derivatives were examined for six human cancer cell lines: HeLaS3, KBvin, MCF-7, HepG2, NCI-H460 and NCI-H460/MX20. Compared to the IC50 values of all the synthesized derivatives, most α,β-unsaturated ketones displayed potent anti-proliferative effects against all six human cancer cell lines, whereas β′-hydroxy-α,β-unsaturated ketones and α,β-unsaturated β-diketones presented moderate anti-proliferative effects. Two potent curcuminoid derivatives were found among all the novel derivatives and reference compounds: (E)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound 3) and (1E,4E)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a). These were selected for further analysis after the evaluation of their anti-proliferative effects against all human cancer cell lines. The results of apoptosis assays revealed that the number of dead cells was increased in early apoptosis and late apoptosis, while cell proliferation was also decreased after applying various concentrations of (E)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound 3) and (1E,4E)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a) to MCF-7 and HpeG2 cancer cells. Analysis of the gene expression arrays showed that three genes (GADD45B, SESN2 and BBC3) were correlated with the p53 pathway. From the quantitative PCR analysis, it was seen that (1E,4E)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a) effectively induced the up-regulated expression of GADD45B, leading to the suppression of MCF-7 cancer cell formation and cell death. Molecular docking analysis was used to predict and sketch the interactions of the GADD45B-α,β-unsaturated ketone complex for help in drug design.
Highlights
The natural product curcumin is a major component of turmeric (Curcuma longa), a spice plant in the ginger family (Zingiberaceae) growing in Asia and it contains several bioactive constituents with various medicinal properties, such as antioxidant and anti-inflammatory properties
Three aspects had to be considered in the design and synthesis of the curcuminoid Three aspects had to be in the design and synthesis the curcuminoid derivatives: the synthesis of considered curcuminoid derivatives with various of aromatic rings for derivatives: the synthesis of curcuminoid derivatives with various aromatic for α,βring ring A, the synthesis of the different scaffolds (β -hydroxy-α,β-unsaturatedrings ketone, A, the synthesis of the different scaffolds (β’-hydroxy-α,β-unsaturated ketone, α,β-ununsaturated β-diketone and α,β-unsaturated ketone) of the curcuminoid derivatives and saturated β-diketone and α,β-unsaturated ketone) of thenumbers curcuminoid derivatives and the the synthesis of curcuminoid derivatives with different of methoxy or hydroxy synthesis curcuminoid derivatives with numbers of methoxy or hydroxy groups onof each of the phenyl rings A and
1–8, 1–8, 10–17 and MD1–12 were synthesized in two parts (Scheme 1)
Summary
The natural product curcumin is a major component of turmeric (Curcuma longa), a spice plant in the ginger family (Zingiberaceae) growing in Asia and it contains several bioactive constituents with various medicinal properties, such as antioxidant and anti-inflammatory properties.
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