Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
| Autor: | Hui-Chang Lin, Chin-Chuan Hung, Chen-Yin Chen, Jin-Cherng Lien, Chien-Yu Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Ketone
curcuminoids Alnus chemistry.chemical_compound curcumin Biology (General) Cytotoxicity Spectroscopy chemistry.chemical_classification Principal Component Analysis α β-unsaturated β-diketone apoptosis General Medicine Ketones Cell cycle GADD45B Computer Science Applications Molecular Docking Simulation Chemistry diarylheptanoids anticancer activity Biochemistry cell cycle p53 pathway Signal Transduction QH301-705.5 Antineoplastic Agents Article Catalysis Inorganic Chemistry Cell Line Tumor Humans Curcuminoid Physical and Theoretical Chemistry QD1-999 Molecular Biology Cell Proliferation Cell growth flow cytometry Organic Chemistry molecular docking Genes p53 Antigens Differentiation Gene Expression Regulation chemistry Apoptosis Drug Design Cancer cell Curcumin gene expression Drug Screening Assays Antitumor |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 22 International Journal of Molecular Sciences, Vol 22, Iss 12171, p 12171 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms222212171 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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