Abstract：
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.
OBJECTIVE: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure.
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.
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.
CONCLUSIONS: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer.
OBJECTIVE: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure.
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.
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.
CONCLUSIONS: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer.
摘要：
背景：焦度，化疗药物引发的细胞死亡过程，近年来，已经成为一种非常有前途的抗肿瘤机制。作为新药的领头羊,天然产物在发现抗癌药物中起着重要作用。与其他天然产品相比，药物食品同源天然产物（MFHNP）表现出优越的安全性。在一系列MFHNP分子骨架中，这项研究发现，只有亚苄基苯乙酮（1）可以诱导癌细胞焦亡。然而,1的抗癌活性有待提高。
目的：本研究旨在通过修饰查尔酮结构寻找一种具有高效抗肿瘤活性的焦亡诱导剂。
方法：为了检查化合物1中迈克尔受体对诱导焦亡的作用，通过修饰迈克尔受体合成了几种类似物。随后，通过MTT法测试抗癌活性，在人肺癌NCI-H460和人卵巢癌CP-70细胞系中观察到了细胞凋亡的形态学指征。此外，为了提高查尔酮骨架的活性，抗癌基团3,4,5-三甲氧基苯基被结合到苯环中。随后，化合物2-22被设计，合成，并在人肺癌细胞(NCI-H460、H1975和A549)中筛选。此外,使用极限梯度增强(XGBoost)机器学习库建立定量构效关系(QSAR)模型,以鉴定药效基团.此外，进行了体外和体内实验，以研究活性化合物诱导的焦亡的分子机制。
结果：α，β-不饱和酮是查尔酮骨架的官能团，在诱导癌细胞焦亡中起关键作用。QSAR模型显示回归系数(R2)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,化合物7被选为活性化合物。此外，发现化合物7通过增加ROS水平上调CHOP的表达来诱导肺癌细胞的焦亡。此外，它有效地抑制了肺癌异种移植瘤的生长。
结论：化合物7通过调节ROS/ER应激/焦亡轴而具有抗肿瘤活性，是一种有前途的焦亡诱导剂。
目的：本研究旨在通过修饰查尔酮结构寻找一种具有高效抗肿瘤活性的焦亡诱导剂。
方法：为了检查化合物1中迈克尔受体对诱导焦亡的作用，通过修饰迈克尔受体合成了几种类似物。随后，通过MTT法测试抗癌活性，在人肺癌NCI-H460和人卵巢癌CP-70细胞系中观察到了细胞凋亡的形态学指征。此外，为了提高查尔酮骨架的活性，抗癌基团3,4,5-三甲氧基苯基被结合到苯环中。随后，化合物2-22被设计，合成，并在人肺癌细胞(NCI-H460、H1975和A549)中筛选。此外,使用极限梯度增强(XGBoost)机器学习库建立定量构效关系(QSAR)模型,以鉴定药效基团.此外，进行了体外和体内实验，以研究活性化合物诱导的焦亡的分子机制。
结果：α，β-不饱和酮是查尔酮骨架的官能团，在诱导癌细胞焦亡中起关键作用。QSAR模型显示回归系数(R2)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,化合物7被选为活性化合物。此外，发现化合物7通过增加ROS水平上调CHOP的表达来诱导肺癌细胞的焦亡。此外，它有效地抑制了肺癌异种移植瘤的生长。
结论：化合物7通过调节ROS/ER应激/焦亡轴而具有抗肿瘤活性，是一种有前途的焦亡诱导剂。
