Design, synthesis, and evaluation of chalcone analogues incorporate α,β-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis

Eur J Med Chem. 2018 Sep 5:157:1395-1405. doi: 10.1016/j.ejmech.2018.08.072.

Min Zhu ¹, Jiabing Wang ², Jingwen Xie ¹, Liping Chen ¹, Xiaoyan Wei ³, Xing Jiang ¹, Miao Bao ⁴, Yanyi Qiu ¹, Qian Chen ¹, Wulan Li ⁵, Chengxi Jiang ¹, Xiaoou Zhou ¹, Liping Jiang ⁶, Peihong Qiu ⁷, Jianzhang Wu ⁸

Affiliations

1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Municipal Hospital Affiliated to Medical School of Taizhou University, Taizhou, Zhejiang, 318000, China.
3 Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
4 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
6 Department of Parasitology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.
7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: wjzwzmc@126.com.
8 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: wjzwzmu@163.com.

PMID: 30196062 DOI: 10.1016/j.ejmech.2018.08.072

Abstract

Chalcone, a natural structure, demonstrates many pharmacological activities including Anticancer, and one promising mechanism is to modulate the generation of ROS. It has been known that Pyroptosis is associated with Anticancer effects, whereas there is fewer researches about ROS-mediated Pyroptosis triggered by chemotherapy drugs. Moreover, incorporation of a α,β-unsaturated ketone unit into chalcone may be an effective strategy for development of chemotherapy drugs. Hence, a number of chalcone analogues bearing a α,β-unsaturated ketone were synthesized from chalcone analogues 1 with modest Anticancer activities as the lead compound. Structure-activity relationship (SAR) studies confirmed the function of α,β-unsaturated ketone to improve Anticancer activity. Notably, compound 8, bearing a α,β-unsaturated ketone, is the most potent inhibitor of Cancer, with IC₅₀ values on NCI-H460, A549 and H1975 cells of 2.3 ± 0.3, 3.2 ± 0.0 and 5.7 ± 1.4 μM, respectively. Besides, 8 showed antiproliferative ability against NCI-H460 cells in a time- and concentration-dependent manner through modulating ROS to induce caspase-3-mediated Pyroptosis, and displayed a better safety profile in vivo. Overall, these results demonstrated that compound 8 is a candidate agent and a potential lead compound for development of chemotherapy drugs, and can be used as a probe to further examine the mechanism of ROS-dependent Pyroptosis.

Keywords

Anticancer effect; Chalcone analogues; Pyroptosis; ROS; α,β-unsaturated ketone.

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