Design, synthesis and biological evaluation of benzo[b]thiophene analogues as novel ferroptosis inhibitor that inhibit fibrosarcoma cell proliferation

Article

作者: Wu, Xiaoya ; Zhu, Ling ; Wang, Yinuo ; Yang, Hua ; Sun, Moran ; Guo, Mingmei ; Guan, Sumeng ; Chang, Yuanyuan

While apoptosis activation has traditionally been considered as an anti-cancer mechanism, current research points to ferroptosis stimulation as a potentially effective cancer therapy. Glutathione peroxidase 4 (GPX4), an essential antioxidant enzyme, serves as a negative regulator of ferroptosis, and its targeted inhibition or degradation can efficiently induce this process. In this study, a potent ferroptosis inducer III-4 that bearing a benzo[b]thiophene moiety was developed by employing a sequential structure optimization process based on RSL-3 to inhibit cancer cells proliferation. At the same time, this cytotoxic activity could be reversed by ferroptosis inducer Fer-1, suggesting that III-4 functions as a ferroptosis inducer. The structure-activity relationship (SAR) of these compounds was also explored. At the cellular level, compound III-4 could block the generation of GSH, cause the accumulation of ROS and MDA, down-regulate GPX4 level, and finally trigger the Fe²⁺-mediated ferroptosis in HT1080 cell lines. Further biological investigation revealed that III-4 arrested the cell cycle at the S phase and inhibited HT1080 cell lines migration. These results indicated that compound III-4 is a candidate for the identification of novel ferroptosis inducer for fibrosarcoma cells.

2025-03-01·International Journal of Pharmaceutics

StatGel: An Innovative hydrogel carrying STAT3-targeted small molecule inhibitor for the treatment of abdominal adhesions

Article

作者: Chen, Fan ; Junjie, Wu ; Qian, Yao ; Yijie, Wang ; Sha, Wan ; Xin, Gu ; Kexin, Tang ; Dan, Song ; Haoxuan, Zhou ; Qin, Zhao ; Xiuzhen, Hu ; Dongping, Yao ; Yongmei, Xie ; Qingquan, Kong ; Qingyu, Dou

Adhesions in the abdominal cavity are among the most common complications post abdominal surgery, resulting from excessive fibrous tissue proliferation and collagen synthesis due to various factors. To date, physical barrier materials have been approved for preventing adhesions, though their effectiveness remains unsatisfactory. One of the important causes of abdominal adhesions is the excessive proliferation of fibrotic cells, and our previous research indicated that STAT3 is a promising therapeutic target for anti-fibrosis. This study designed and synthesized a STAT3 targeted small molecule inhibitor compound 16 K and evaluated its anti-fibrotic effects using the CCK-8 assay on fibroblasts. Compound 16 K was then combined with GelMA (methacryloyl gelatin) hydrogel through UV curing to prepare StatGel, a 16 K-loaded hydrogel with both anti-fibrotic activity and physical barrier properties. Material property assessments showed that StatGel does not alter the inherent properties of GelMA while maintaining the capability of sustained release of compound 16 K. StatGel significantly inhibited the proliferation of L929 cells and TGF-β1-induced fibrotic differentiation, and down-regulated p-STAT3 protein without affecting the STAT3 protein. Furthermore, StatGel was demonstrated to prevent the formation of abdominal adhesions in a mouse model induced by CLP as assessed by histological examination and adhesion index. Overall, StatGel offers a potential approach for effectively preventing the formation of abdominal adhesions.

2025-03-01·Journal of Molecular Structure

Synthesis, fluorescence properties of novel thiazolo[3,2-b][1,2,4]triazol derivatives as potent SHP2 inhibitors and its uses in sensing for Fe3+ and cell imaging

作者: Gao, Li-Xin ; Yan, Xue ; Li, Jia ; Cao, Zi-Tong ; Gan, Su-Ya ; Zhou, Yu-Bo ; Wang, Wen-Long ; Zhang, Chun ; Xiang, Da-Jun

A series of thiazolo[3,2-b][1,2,4]triazole derivatives containing salicylic acid fragment were designed and synthesized.Then, their optical properties and biol. activities were evaluated.Among them, the representative compound 5-2k exhibited higher selectivity/specificity for Fe3+, a low limit of detection (LOD) of 8.2 μM and moderate inhibitory activity against SHP2 with IC50 of 2.85±0.50 μM.Moreover, the activities of SHP1, SHP2, PTP1B and TCPTP enzyme could be adjusted effectively through the interaction between compound 5-2k and metal ion Fe3+.Furthermore, compound 5-2k had low cytotoxicity for peripheral blood mononuclear cell (PBMC) and excellent blue signal in HeLa cell imaging.These results are expected to facilitate the development of novel sensitive and specific fluorescence sensors for Fe3+ and SHP2 inhibitor for cancer therapy.

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适应症	最高研发状态	国家/地区	公司	日期
高钙血症	临床1期	-	Abeona Therapeutics, Inc.	-
高钙血症	临床1期	-	Colgate-Palmolive Co.	-
畸形性骨炎	临床1期	-	Colgate-Palmolive Co.	-
畸形性骨炎	临床1期	-	Abeona Therapeutics, Inc.	-
绝经期后骨质疏松	临床1期	-	Abeona Therapeutics, Inc.	-
绝经期后骨质疏松	临床1期	-	Colgate-Palmolive Co.	-