Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy.
Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation.
['Qian|Jianqiang|J|', 'Xu|Zhongyuan|Z|', 'Meng|Chi|C|', 'Liu|Ji|J|', 'Hsu|Pei-Ling|PL|', 'Li|Yangyang|Y|', 'Zhu|Weizhong|W|', 'Yang|Yumin|Y|', 'Morris-Natschke|Susan L|SL|', 'Lee|Kuo-Hsiung|KH|', 'Zhang|Yanan|Y|', 'Ling|Yong|Y|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D001343:Autophagy D045744:Cell Line, Tumor D003512:Cyclohexanones D015195:Drug Design D004791:Enzyme Inhibitors D005260:Female D006801:Humans D051379:Mice D008807:Mice, Inbred BALB C D008813:Mice, Inbred ICR D017382:Reactive Oxygen Species D013329:Structure-Activity Relationship D013880:Thioredoxin-Disulfide Reductase D023041:Xenograft Model Antitumor Assays
Benzylidenecyclohexenones Reactive oxygen species (ROS) Piperlongumine Thioredoxin reductase (TrxR) Antitumor activities