Small-molecule agents for treating skin diseases
Eur J Med Chem. 2024 Feb 24;268:116269. doi: 10.1016/j.ejmech.2024.116269. Online ahead of print.ABSTRACTSkin diseases are a class of common and frequently occurring diseases that significantly impact daily lives. Currently, the limited effective therapeutic drugs are far from meeting the clinical needs; most drugs typically only provide symptomatic relief rather than a cure. Developing small-molecule drugs with improved efficacy holds paramount importance for treating skin diseases. This review aimed to systematically introduce the pathogenesis of common skin diseases in daily life, list related drugs applied in the clini...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Hong Cai Hao Wen Junjie Li Liuxin Lu Wenxuan Zhao Xiaoying Jiang Renren Bai Source Type: research

Discovery of novel osthole derivatives exerting anti-inflammatory effect on DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice
In this study, 26 osthole derivatives were synthesized, and their anti-inflammatory properties were evaluated. The preliminary activity study revealed that most osthole derivatives could effectively inhibit inflammatory cytokines IL-6 secretion in LPS stimulated mouse macrophages J774A.1. Compound 7m exhibited the most effective anti-inflammatory activity (RAW264.7 IL-6 IC50: 4.57 μM, 32 times more active than osthole) in vitro with no significant influence on cell proliferation. Additionally, the mechanistic analysis demonstrated that compound 7m could block MAPK signal transduction by inhibiting the phosphorylation of J...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Ying Zhou Zhiteng Du Qianqian Wu Mi Guo Zhichao Chen Chenhui Sun Xiaobo Li Yu Zou Zhiwei Zheng Pan Chen Won-Jea Cho Young-Chang Cho Nipon Chattipakorn Yi Wang Guang Liang Qidong Tang Source Type: research

Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer
Eur J Med Chem. 2024 Feb 24;268:116240. doi: 10.1016/j.ejmech.2024.116240. Online ahead of print.ABSTRACTTraf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/β-catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/β-catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1H-imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening. Among them, 35b exhibited excellent TNI...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Yaxin Teng Rui Wu Weichen Bo Minghai Tang TaiJin Wang Xue Cui Yong Li Chufeng Zhang Ziyan Ma Zhiyuan Fu Qing Xu Jie Liu Lijuan Chen Source Type: research

Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice
This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.PMID:38422699 | DOI:10.1016/j.ejmech.2024.116251 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Shiyi Yin Mengmeng Shen Yongjiang Zhang Jiannan Wu Run Song Xiaoyi Lai Zhenzhen Tian Tingting Wang Weina Jin Junqiang Yan Source Type: research

Discovery of novel urea derivatives as ferroptosis and autophagy inducer for human colon cancer treatment
Eur J Med Chem. 2024 Feb 24;268:116277. doi: 10.1016/j.ejmech.2024.116277. Online ahead of print.ABSTRACTA series of novel urea derivatives were designed, synthesized and evaluated for their inhibitory activities against HT-29 cells, and structure-activity relationships (SAR) were summarized. Compound 10p stood out from these derivatives, exhibiting the most potent antiproliferative activity. Further biological studies demonstrated that 10p arrested cell cycle at G2/M phase via regulating cell cycle-related proteins CDK1 and Cyclin B1. The underlying molecular mechanisms demonstrated that 10p induced cell death through fer...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Tingting Liang Haiyang Dong Zhuangzhuang Wang Lu Lu Xueting Song Jianguo Qi Yahong Zhang Jianhong Wang Guanhua Du Source Type: research

Recent advances and mechanisms of action of PD-L1 degraders as potential therapeutic agents
Eur J Med Chem. 2024 Feb 23;268:116267. doi: 10.1016/j.ejmech.2024.116267. Online ahead of print.ABSTRACTPD-L1 is an important immune checkpoint protein that can bind to T cells' PD-1 receptor, thereby promoting immune escape from tumors. In recent years, many researchers have developed strategies to degrade PD-L1 to improve the effect of immunotherapy. The study of degrading PD-L1 provides new opportunities for immunotherapy. Here, we mainly summarize and review the current active molecules and mechanisms that mediate the degradation of immature and mature PD-L1 during the post-translational modification stages, involving...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Feng Zhang Ruiya Jiang Shishi Sun Caiyun Wu Qimeng Yu Annoor Awadasseid Jianwei Wang Wen Zhang Source Type: research

Small-molecule agents for treating skin diseases
Eur J Med Chem. 2024 Feb 24;268:116269. doi: 10.1016/j.ejmech.2024.116269. Online ahead of print.ABSTRACTSkin diseases are a class of common and frequently occurring diseases that significantly impact daily lives. Currently, the limited effective therapeutic drugs are far from meeting the clinical needs; most drugs typically only provide symptomatic relief rather than a cure. Developing small-molecule drugs with improved efficacy holds paramount importance for treating skin diseases. This review aimed to systematically introduce the pathogenesis of common skin diseases in daily life, list related drugs applied in the clini...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Hong Cai Hao Wen Junjie Li Liuxin Lu Wenxuan Zhao Xiaoying Jiang Renren Bai Source Type: research

Discovery of novel osthole derivatives exerting anti-inflammatory effect on DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice
In this study, 26 osthole derivatives were synthesized, and their anti-inflammatory properties were evaluated. The preliminary activity study revealed that most osthole derivatives could effectively inhibit inflammatory cytokines IL-6 secretion in LPS stimulated mouse macrophages J774A.1. Compound 7m exhibited the most effective anti-inflammatory activity (RAW264.7 IL-6 IC50: 4.57 μM, 32 times more active than osthole) in vitro with no significant influence on cell proliferation. Additionally, the mechanistic analysis demonstrated that compound 7m could block MAPK signal transduction by inhibiting the phosphorylation of J...
Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Ying Zhou Zhiteng Du Qianqian Wu Mi Guo Zhichao Chen Chenhui Sun Xiaobo Li Yu Zou Zhiwei Zheng Pan Chen Won-Jea Cho Young-Chang Cho Nipon Chattipakorn Yi Wang Guang Liang Qidong Tang Source Type: research

Identification of a ferritinophagy inducer via sinomenine modification for the treatment of colorectal cancer
Eur J Med Chem. 2024 Feb 21;268:116250. doi: 10.1016/j.ejmech.2024.116250. Online ahead of print.ABSTRACTFerritinophagy is a cellular process to release redox-active iron. Excessive activation of ferritinophagy ultimately results in ferroptosis characterized by ROS accumulation which plays important roles in the development and progression of cancer. Sinomenine, a main bioactive alkaloid from the traditional Chinese medicine Sinomenum acutum, inhibits the proliferation of cancer cells by promoting ROS production. Herein, new compounds were designed and synthesized through the stepwise optimization of sinomenine. Among them...
Source: European Journal of Medicinal Chemistry - February 28, 2024 Category: Chemistry Authors: Ling Zhu Chen Chen Yuxing Cai Yalin Li Lijie Gong Tianyu Zhu Lingyi Kong Jianguang Luo Source Type: research

Chemistry and pharmacological aspects of furanoid cannabinoids and related compounds: Is furanoid cannabinoids open a new dimension towards the non-psychoactive cannabinoids?
Eur J Med Chem. 2024 Feb 9;268:116164. doi: 10.1016/j.ejmech.2024.116164. Online ahead of print.ABSTRACTCannabinoids have emerged as compelling candidates for medicinal applications, notably following the recent approval of non-psychoactive cannabidiol (CBD) as a medicine. This endorsement has stimulated a growing interest in this class of compounds for drug discovery. Within the cannabis plant, a rich reservoir of over 125 compounds exists. Tetrahydrocannabinol (THC), a member of the dibenzopyran class, is widely recognized for its psychoactive effects. Conversely, the furanoid class, represented by cannabielsoin-type (CB...
Source: European Journal of Medicinal Chemistry - February 28, 2024 Category: Chemistry Authors: Radhika Anand Ritu Painuli Vijay Kumar Parvinder Pal Singh Source Type: research

Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs
In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC50 of 0.81 μM and 0.84 μM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung cancer cells, and induces s-phase cell c...
Source: European Journal of Medicinal Chemistry - February 27, 2024 Category: Chemistry Authors: Lianhua Piao Ying Gao Xiaoshuang Xu Yangyang Su Yanong Daniel Wang Jie Zhou Yang Gao Jin Fang Qihui Li Shan Chang Ren Kong Source Type: research

Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs
In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC50 of 0.81 μM and 0.84 μM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung cancer cells, and induces s-phase cell c...
Source: European Journal of Medicinal Chemistry - February 27, 2024 Category: Chemistry Authors: Lianhua Piao Ying Gao Xiaoshuang Xu Yangyang Su Yanong Daniel Wang Jie Zhou Yang Gao Jin Fang Qihui Li Shan Chang Ren Kong Source Type: research

Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus (MRSA) infections
Eur J Med Chem. 2024 Feb 21;268:116274. doi: 10.1016/j.ejmech.2024.116274. Online ahead of print.ABSTRACTMethicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Here, a series of novel isoxanthohumol-amine conjugates were synthesized as antibacterials. After bioactivity evaluation, a compound E2 was obtained, which showed excellent antibacterial activity against S. aureus and clinical MRSA isolates (MICs = 0.25-1 μg/mL), superior to vancomycin, and with negligibl...
Source: European Journal of Medicinal Chemistry - February 26, 2024 Category: Chemistry Authors: Ruige Yang Wanqing Cheng Meijuan Huang Ting Xu Miaomiao Zhang Jifeng Liu Shangshang Qin Yong Guo Source Type: research

Comprehensive review on the elaboration of payloads derived from natural products for antibody-drug conjugates
Eur J Med Chem. 2024 Feb 22;268:116233. doi: 10.1016/j.ejmech.2024.116233. Online ahead of print.ABSTRACTAntibody-drug conjugates (ADCs) have arisen as a promising class of biotherapeutics for targeted cancer treatment, combining the specificity of monoclonal antibodies with the cytotoxicity of small-molecule drugs. The choice of an appropriate payload is crucial for the success development of ADCs, as it determines the therapeutic efficacy and safety profile. This review focuses on payloads derived from natural products, including cytotoxic agents, DNA-damaging agents, and immunomodulators. These offer several advantages ...
Source: European Journal of Medicinal Chemistry - February 26, 2024 Category: Chemistry Authors: Nan Lu Jiaqi Wu Mengwei Tian Shanshan Zhang Zhiguo Li Liming Shi Source Type: research

Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus (MRSA) infections
Eur J Med Chem. 2024 Feb 21;268:116274. doi: 10.1016/j.ejmech.2024.116274. Online ahead of print.ABSTRACTMethicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Here, a series of novel isoxanthohumol-amine conjugates were synthesized as antibacterials. After bioactivity evaluation, a compound E2 was obtained, which showed excellent antibacterial activity against S. aureus and clinical MRSA isolates (MICs = 0.25-1 μg/mL), superior to vancomycin, and with negligibl...
Source: European Journal of Medicinal Chemistry - February 26, 2024 Category: Chemistry Authors: Ruige Yang Wanqing Cheng Meijuan Huang Ting Xu Miaomiao Zhang Jifeng Liu Shangshang Qin Yong Guo Source Type: research