School of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Road, Beitun Dist., Taichung 406040, Taiwan.
Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan.
Int J Mol Sci. 2021 Nov 10;22(22):12171. doi: 10.3390/ijms222212171.
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 IC 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: ()-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound ) and (1,4)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound ). 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 ()-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound ) and (1,4)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound ) 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 (1,4)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound ) 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.
姜黄素和姜黄素类化合物由于其具有重要生物活性的功能团（如α,β-不饱和β-二酮、α,β-不饱和酮和β'-羟基-α,β-不饱和酮与两侧芳环相连的结构）而备受关注，包括抗氧化、抗炎、抗增殖和抗癌活性。使用三步有机合成法，以较高的产率合成了一系列新型姜黄素衍生物（共 55 个新化合物）和三个参考化合物。对六种人癌细胞系（HeLaS3、KBvin、MCF-7、HepG2、NCI-H460 和 NCI-H460/MX20）进行了姜黄素衍生物的抗增殖活性检测。与所有合成衍生物的 IC 值相比，大多数α,β-不饱和酮对所有六种人癌细胞系均表现出较强的抗增殖作用，而β'-羟基-α,β-不饱和酮和α,β-不饱和β-二酮则表现出中等的抗增殖作用。在所研究的所有新型衍生物和参考化合物中，发现了两种有效的姜黄素衍生物：()-5-羟基-7-苯基-1-(3,4,5-三甲氧基苯基)庚-1-烯-3-酮（化合物）和(1,4)-1,7-双(3,4,5-三甲氧基苯基)庚-1,4-二烯-3-酮（化合物）。在评估了它们对所有人类癌细胞系的抗增殖作用后，选择了这两种化合物进行进一步分析。细胞凋亡分析的结果表明，应用不同浓度的()-5-羟基-7-苯基-1-(3,4,5-三甲氧基苯基)庚-1-烯-3-酮（化合物）和(1,4)-1,7-双(3,4,5-三甲氧基苯基)庚-1,4-二烯-3-酮（化合物）后，早期和晚期凋亡的死亡细胞数量增加，而细胞增殖也减少。基因表达谱分析表明，三个基因（GADD45B、 SESN2 和 BBC3）与 p53 途径相关。从定量 PCR 分析可以看出，(1,4)-1,7-双(3,4,5-三甲氧基苯基)庚-1,4-二烯-3-酮（化合物）有效诱导 GADD45B 的上调表达，从而抑制 MCF-7 癌细胞的形成和死亡。分子对接分析用于预测和描绘 GADD45B-α,β-不饱和酮复合物的相互作用，以帮助药物设计。
