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新型单羰基姜黄素类似物在肝癌细胞中的设计、合成及抗肿瘤评价

Design, Synthesis, and Antitumor Evaluation of Novel Mono-Carbonyl Curcumin Analogs in Hepatocellular Carcinoma Cell.

作者信息

Yu Pan, Cao Weiya, Zhao Linguo, Han Qing, Yang Shilong, Yang Kepeng, Pan Xiaolei, Wang Qianyun, Wang Yuan

机构信息

College of Medicine, Anhui University of Science and Technology, Huainan 232001, China.

College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China.

出版信息

Pharmaceuticals (Basel). 2022 Jul 30;15(8):950. doi: 10.3390/ph15080950.

DOI:10.3390/ph15080950
PMID:36015097
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9413278/
Abstract

Curcumin is a polyphenolic natural product that has promising anticancer properties. However, its clinical utility is limited by its chemical instability and poor metabolic properties. In this paper, a series of new curcumin analogs were synthesized and found to be potent antiproliferative agents against the HepG2 cell line by MTT assay. In general, Group B with single ketone and group C with chalcone were markedly more cytotoxic than group A with diketone. Compound was found as the most potent analog (IC = 11.33 μM) compared to curcumin (IC = 32.83 μM) and the mechanism of its cytotoxicity was investigated. The result of the wound healing assay indicated strong potential to suppress HepG2 cell migration in a dose- and time-dependent manner. Subsequent assays (including JC-1 staining, Bcl-2, and caspase 3 protein levels by Western blotting) confirmed that exposure induced apoptosis in HepG2 cells. Curcumin-induced comprehensive transcriptomes profile, Western blotting, molecular docking, and molecular dynamics analysis showed that the mechanism may relate to the regulation of cellular metabolic process and the expression of AKT protein. Taken together, we could conclude that curcumin and its analogs induced HepG2 cell proliferation, migration, and apoptosis via AKT signaling pathway and the mitochondrial death pathway. This study could lay the foundation for optimizing curcumin and provide valuable information for finding novel anti-HCC drugs.

摘要

姜黄素是一种具有潜在抗癌特性的多酚类天然产物。然而，其化学不稳定性和较差的代谢特性限制了其临床应用。本文合成了一系列新的姜黄素类似物，并通过MTT法发现它们是针对HepG2细胞系的有效抗增殖剂。一般来说，含单酮的B组和含查尔酮的C组的细胞毒性明显高于含二酮的A组。与姜黄素（IC = 32.83 μM）相比，化合物 被发现是最有效的类似物（IC = 11.33 μM），并对其细胞毒性机制进行了研究。伤口愈合试验结果表明， 具有以剂量和时间依赖性方式抑制HepG2细胞迁移的强大潜力。随后的试验（包括JC-1染色、通过蛋白质印迹法检测Bcl-2和半胱天冬酶3蛋白水平）证实， 处理可诱导HepG2细胞凋亡。姜黄素诱导的综合转录组图谱、蛋白质印迹法、分子对接和分子动力学分析表明，其机制可能与细胞代谢过程的调节和AKT蛋白的表达有关。综上所述，我们可以得出结论，姜黄素及其类似物通过AKT信号通路和线粒体死亡通路诱导HepG2细胞增殖、迁移和凋亡。本研究可为优化姜黄素奠定基础，并为寻找新型抗肝癌药物提供有价值的信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/e04d3ec00cb6/pharmaceuticals-15-00950-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/190c2a2d8363/pharmaceuticals-15-00950-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/48e4dfeff265/pharmaceuticals-15-00950-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/d300ed654227/pharmaceuticals-15-00950-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/aad801c3e29c/pharmaceuticals-15-00950-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/339e02e5f697/pharmaceuticals-15-00950-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/613d818c5328/pharmaceuticals-15-00950-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/efac92faea88/pharmaceuticals-15-00950-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/137283136e4c/pharmaceuticals-15-00950-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/5571211b094d/pharmaceuticals-15-00950-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/e04d3ec00cb6/pharmaceuticals-15-00950-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/190c2a2d8363/pharmaceuticals-15-00950-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/48e4dfeff265/pharmaceuticals-15-00950-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/d300ed654227/pharmaceuticals-15-00950-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/aad801c3e29c/pharmaceuticals-15-00950-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/339e02e5f697/pharmaceuticals-15-00950-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/613d818c5328/pharmaceuticals-15-00950-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/efac92faea88/pharmaceuticals-15-00950-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/137283136e4c/pharmaceuticals-15-00950-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/5571211b094d/pharmaceuticals-15-00950-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edd3/9413278/e04d3ec00cb6/pharmaceuticals-15-00950-g007.jpg

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