Background: Pyroptosis, a cell death process triggered by chemotherapy drugs, has emerged as a highly promising mechanism for combating tumors in recent years. As the lead of new drugs, natural products play an important role in the discovery of anticancer drugs. Compared to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior safety profile. Among a series of MFHNP molecular skeletons, this study found that only benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity of 1 remains to be improved. background: Pyroptosis induced by chemotherapy drugs is a promising antitumor mechanism discovered in recent years. Natural products as the lead for new drugs dicovery still remains an important role for the discovery of anticancer drugs. Compared to others natural products, the medicine food homologous natural products (MFHNP) have better safety profile. Among a series of MFHNP molecular skeletons, this study found that only benzylideneacetophenone (1) could induce cancer cell pyroptosis.However, the anti-cancer activity of 1 remains to be improved. Aims: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure. objective: / Methods: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis, several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer activity was tested by MTT assay, and morphological indications of pyroptosis were observed in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore, to improve the activity of the chalcone skeleton, the anticancer group 3,4,5- trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed, synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally, a quantitative structure-activity relationship (QSAR) model was established using the eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore. Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular mechanisms of pyroptosis induced by the active compound. method: To examine the effect of the michael receptor in compound 1 on the induction of pyroptosis, some analogs were synthezised by modifying the michael acceptor, the anti-cancer activity was tested by MTT assay and morphologic signs of pyroptosis were observed in NCI-H460 and CP-70 cell lines. Furthermore, to improve the activity of chalcone skeleton, the anti-cancer group 3,4,5-trimethoxyphenyl was introduced to the phenyl ring, and compounds 2-22 were designed, synthesized and screened in lung cancers. The quantitative structure-activity relationship (QSAR) model was established by XGBoost method of artificial intelligence to identify the pharmacophore. Experiments In vitro and in vivo were performed to explore the molecular mechanism of pyroptosis induced by the active compound. Results: α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients (R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft tumors. result: α, β-unsaturated ketone was the functional group of chalcone skeleton and played a pivotal role in inducing cancer cells pyroptosis.QSAR models shown that the regression coefficient R2 were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these compounds, compound 7 was selected to be active compound. Moreover, Compound 7 triggered pyroptosis of lung cancer cells by inducing the expression of CHOP via elevating the ROS level, and effectively restrained the xenograft tumor growth of lung cancer. Conclusion: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer. conclusion: Compound 7 exhibits antineoplastic activity by regulation of the ROS/ER stress/Pyroptosis axis, is a kind of promising pyroptosis inducer.

中文翻译：

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基于 ROS/ER 应激/焦亡轴发现焦亡诱导药物和抗肿瘤活性

背景：焦亡是一种由化疗药物引发的细胞死亡过程，近年来已成为一种非常有前景的抗肿瘤机制。天然产物作为新药的领头羊，在抗癌药物的发现中发挥着重要作用。与其他天然产物相比，药食同源天然产物（MFHNP）表现出优越的安全性。在一系列MFHNP分子骨架中，本研究发现只有亚苄基苯乙酮(1)能够诱导癌细胞焦亡。但1的抗癌活性仍有待提高。背景：化疗药物诱导的焦亡是近年来发现的一种有前景的抗肿瘤机制。天然产物作为新药发现的先导仍然在抗癌药物的发现中发挥着重要作用。与其他天然产物相比，药食同源天然产物（MFHNP）具有更好的安全性。在一系列MFHNP分子骨架中，本研究发现只有亚苄基苯乙酮(1)能够诱导癌细胞焦亡。但1的抗癌活性还有待提高。目的：本研究旨在通过修饰查尔酮结构来寻找具有高效抗肿瘤活性的细胞焦亡诱导剂。目的：/方法：为了检查化合物1中的Michael受体对诱导细胞焦亡的作用，通过修饰Michael受体合成了几种类似物。随后，通过MTT法检测其抗癌活性，并在人肺癌NCI-H460和人卵巢癌CP-70细胞系中观察到细胞焦亡​​的形态学迹象。此外，为了提高查尔酮骨架的活性，将抗癌基团3,4,5-三甲氧基苯基纳入苯环中。随后，设计、合成了化合物2-22，并在人肺癌细胞（NCI-H460、H1975和A549）中进行筛选。此外，使用 eXtreme Gradient Boosting (XGBoost) 机器学习库建立了定量构效关系 (QSAR) 模型来识别药效团。此外，还进行了体外和体内实验来研究活性化合物诱导细胞焦亡的分子机制。方法：为了考察化合物1中迈克尔受体对细胞焦亡的诱导作用，通过修饰迈克尔受体合成了一些类似物，通过MTT法检测其抗癌活性，并在NCI-H460中观察细胞焦亡的形态学征象。和 CP-70 细胞系。此外，为了提高查尔酮骨架的活性，在苯环上引入了抗癌基团3,4,5-三甲氧基苯基，设计、合成并筛选了化合物2-22，并在肺癌中进行了筛选。利用人工智能XGBoost方法建立定量构效关系（QSAR）模型来识别药效基团。进行体外和体内实验以探索活性化合物诱导细胞焦亡的分子机制。结果：α,β-不饱和酮是查耳酮骨架的官能团，在诱导癌细胞焦亡中发挥着关键作用。QSAR 模型显示回归系数 (R2) 分别为 0.992（A549 细胞）、0.990（NCI-H460 细胞）和 0.998（H1975 细胞）。在这些化合物中，选择化合物7作为活性化合物。此外，化合物7被发现通过增加ROS水平上调CHOP的表达来诱导肺癌细胞焦亡。此外，它还有效抑制肺癌异种移植肿瘤的生长。结果：α,β-不饱和酮是查耳酮骨架的功能基团，在诱导癌细胞焦亡中起关键作用。QSAR模型显示回归系数R2分别为0.992（A549细胞）、0.990（NCI-H460细胞）、0.990（NCI-H460细胞）。 0.998（H1975 细胞）。在这些化合物中，选择化合物7作为活性化合物。此外，化合物7通过升高ROS水平诱导CHOP表达，引发肺癌细胞焦亡，有效抑制肺癌异种移植瘤的生长。结论：化合物7通过调节ROS/ER应激/焦亡轴发挥抗肿瘤活性，是一种有前景的焦亡诱导剂。结论：化合物7通过调节ROS/ER应激/细胞焦亡轴发挥抗肿瘤活性，是一种有前景的细胞焦亡诱导剂。