In the present work, the mechanism of anticancer activity of some pyrrolopyrimidine derivatives was evaluated. Compounds 5 and 8 exhibiting significant antiproliferative activity against HT-29 cells with IC₅₀ values of 4.17 μM and 2.96, arrested the cells at the G2/M phase and significantly induced apoptosis. The apoptotic potential of the compounds has been verified via ELISA assay, which resulted in increased BAX, PUMA, BIM, and cleaved caspase 3 expression and decreased BCL-XL and MCL-1 protein levels in HT-29 cells. Moreover, the immunofluorescence technique showing that compounds 5 and 8-treatment reduced Ki67 immunolocalization and increased the caspase 3 and p53 immunolocalization confirmed the apoptotic activity. While treatment of HT-29 cells to compounds 5 and 8 inhibited Akt and ERK1/2, there are no alterations in JNK and p38 signaling pathways. According to molecular docking results, compounds 5 and 8 occupied the active site of Akt kinase and showed important hydrogen bonding interactions with key amino acids. Also, siRNA-mediated depletion of BIM, PUMA, and BAX/BAK expression decreased apoptotic response in HT-29 cells upon exposure to compound 5 and compound 8. Compounds 5 and 8 trigger the activation of mitochondrial apoptosis in HT-29 cells. Additionally, we found that proapoptotic BH3-only proteins BIM and PUMA are required for the full engagement of mitochondrial apoptosis signaling. However, p53 was dispensable for compound 5- or compound 8-induced apoptosis in HT-29 cells.

2024-03-01·Bioorganic Chemistry

Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene

Article

作者: Chen, Xueqin ; Xiao, Tianyichen ; Liu, Jie ; Hong, Wenbin ; Li, Hailong ; Liang, Zhijian ; Liu, Changqin ; Wang, Songqing ; Lin, Tianwei ; Li, Yunlong ; Lin, Gang ; Hu, Hongyu ; Wu, Siqi

Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-β1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.

2024-01-01·European Journal of Medicinal Chemistry

Design and synthesis of pterostilbene derivatives bearing triazole moiety that might treat DSS-induced colitis in mice through modulation of NF-κB/MAPK signaling pathways

Article

作者: Liu, Xiaohan ; Wang, Lifan ; Chen, Liuzeng ; Wang, Wei ; Li, Jia ; Ruan, Banfeng ; Wang, Mengya ; Wang, Lingyun ; Wang, Ke

In this study, a series of novel anti-inflammatory compounds with high activity and low toxicity were designed and synthesized based on the natural product pterostilbene skeleton. According to the strategy of pharmacophore combination, we introduced thiazole moiety into pterostilbene skeleton to design and synthesize a novel series of pterostilbene derivatives (a total of 41 compounds), and lipopolysaccharide (LPS)-treated RAW 264.7 cells were screened for anti-inflammatory activity and cytotoxicity. Among them, compound 8 was found to be the most active (against NO: IC₅₀ = 0.6 μM) compared with pterostilbene and indomethacin. Anti-inflammatory mechanism studies revealed that compound 8 inhibited pro-inflammatory cytokines by blocking the NF-κB/MAPK signaling pathway in LPS-treated RAW 264.7 cells. In vivo experiments showed that compound 8 had a good relieving effect on DSS-induced acute colitis in mice, and also demonstrated a good safety in acute toxicity experiments. In conclusion, compound 8 may be a promising anti-inflammatory lead compound in the treatment of acute colitis.

100 项与 Compound 8a(Wichita State University) 相关的药物交易

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