Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy
Eur J Med Chem. 2022 Jun 15;239:114530. doi: 10.1016/j.ejmech.2022.114530. Online ahead of print.ABSTRACTNatural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3'-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor ac...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Ziyi Liang Yuqing Wang Honghua Zhang Jiedan Deng Fang Lei Junfang Li Tao Shi Shuzhi Wang Ranhui Li Zhen Wang Source Type: research

Recent advances in the development of EGFR degraders: PROTACs and LYTACs
Eur J Med Chem. 2022 Jun 16;239:114533. doi: 10.1016/j.ejmech.2022.114533. Online ahead of print.ABSTRACTEpidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting C...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Dawei Hong Bizhong Zhou Bei Zhang Hao Ren Liquan Zhu Guowan Zheng Minghua Ge Jingyan Ge Source Type: research

A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement
In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM, and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Qi Li Baichen Xiong Yuanyuan Wang Weiping Lyu Shuaishuai Xing Ying Chen Qinghong Liao Siyu He Feng Feng Wenyuan Liu Yao Chen Haopeng Sun Source Type: research

Bis-chalcone polyphenols with potential preventive and therapeutic effects on PD: Design, synthesis and in vitro disaggregation activity against α-synuclein oligomers and fibrils
Eur J Med Chem. 2022 Jun 16;239:114529. doi: 10.1016/j.ejmech.2022.114529. Online ahead of print.ABSTRACTα-Syn fibrils, which are neurotoxic, play a key role in the development of PD. Maintaining α-Syn proteostasis by suitable molecule ligands is an effective approach to prevent aggregation. Disintegrating the existed oligomers and fibrils into individual α-Syn by small molecular compounds is a more efficient way to treat PD. This work designed and synthesized two series of bis-chalcone polyphenol compounds, which possess a sheet-like conjugated skeleton with stronger H-bonding, π-stacking, and hydrophobic interaction ...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Bing Jiang Feng Han Ming-Huan L ü Zhen-Ping Wang Wei Liu Yun-Xiao Zhang Ji Xu Rui-Jun Li Source Type: research

Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy
Eur J Med Chem. 2022 Jun 15;239:114530. doi: 10.1016/j.ejmech.2022.114530. Online ahead of print.ABSTRACTNatural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3'-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor ac...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Ziyi Liang Yuqing Wang Honghua Zhang Jiedan Deng Fang Lei Junfang Li Tao Shi Shuzhi Wang Ranhui Li Zhen Wang Source Type: research

Recent advances in the development of EGFR degraders: PROTACs and LYTACs
Eur J Med Chem. 2022 Jun 16;239:114533. doi: 10.1016/j.ejmech.2022.114533. Online ahead of print.ABSTRACTEpidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting C...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Dawei Hong Bizhong Zhou Bei Zhang Hao Ren Liquan Zhu Guowan Zheng Minghua Ge Jingyan Ge Source Type: research

A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement
In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM, and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Qi Li Baichen Xiong Yuanyuan Wang Weiping Lyu Shuaishuai Xing Ying Chen Qinghong Liao Siyu He Feng Feng Wenyuan Liu Yao Chen Haopeng Sun Source Type: research

Bis-chalcone polyphenols with potential preventive and therapeutic effects on PD: Design, synthesis and in vitro disaggregation activity against α-synuclein oligomers and fibrils
Eur J Med Chem. 2022 Jun 16;239:114529. doi: 10.1016/j.ejmech.2022.114529. Online ahead of print.ABSTRACTα-Syn fibrils, which are neurotoxic, play a key role in the development of PD. Maintaining α-Syn proteostasis by suitable molecule ligands is an effective approach to prevent aggregation. Disintegrating the existed oligomers and fibrils into individual α-Syn by small molecular compounds is a more efficient way to treat PD. This work designed and synthesized two series of bis-chalcone polyphenol compounds, which possess a sheet-like conjugated skeleton with stronger H-bonding, π-stacking, and hydrophobic interaction ...
Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Bing Jiang Feng Han Ming-Huan L ü Zhen-Ping Wang Wei Liu Yun-Xiao Zhang Ji Xu Rui-Jun Li Source Type: research

Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer
Eur J Med Chem. 2022 Jun 2;239:114504. doi: 10.1016/j.ejmech.2022.114504. Online ahead of print.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized tha...
Source: European Journal of Medicinal Chemistry - June 20, 2022 Category: Chemistry Authors: Jian-Fei Bai Somi Reddy Majjigapu Bernard Sordat Sophie Poty Pierre Vogel Pilar El ías-Rodríguez Antonio J Moreno-Vargas Ana T Carmona Irene Caffa Moustafa Ghanem Amr Khalifa Fiammetta Monacelli Michele Cea Inmaculada Robina Consuelo Gajate Faustino Mol Source Type: research

Marine natural products and their synthetic analogs as promising antibiofilm agents for antibiotics discovery and development
Eur J Med Chem. 2022 Jun 4;239:114513. doi: 10.1016/j.ejmech.2022.114513. Online ahead of print.ABSTRACTBiofilm is a complex microbial consortium that are embedded in a membrane structure of the extracellular polymeric substances (EPS). As a major form of microorganisms in nature, biofilm has evolved complex and diverse resistance mechanisms to numerous known antibiotics, posing a major threat to human health. The biofilm formation of pathogens including Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, etc. has become the most commonly reasons for clinically chronic and incurable infectious diseases, whi...
Source: European Journal of Medicinal Chemistry - June 20, 2022 Category: Chemistry Authors: Yueting Deng Yang Liu Juan Li Xiao Wang Shan He Xiaojun Yan Yutong Shi Weiyan Zhang Lijian Ding Source Type: research

Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase
Eur J Med Chem. 2022 Jun 13;239:114528. doi: 10.1016/j.ejmech.2022.114528. Online ahead of print.ABSTRACTNuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC50 values of 1.43 and 0.94 μM in NCI-H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and ...
Source: European Journal of Medicinal Chemistry - June 19, 2022 Category: Chemistry Authors: Yaoliang Sun Ying Zhang Xiaoai Chen Aisong Yu Wenhao Du Yuting Huang Feifei Wu Lei Yu Jiayi Li Cuiyun Wen Hong Yang Qiongyu Shi Meiyu Geng Xun Huang Shilin Xu Source Type: research

Azole inhibitors of mushroom and human tyrosinases: Current advances and prospects of drug development for melanogenic dermatological disorders
Eur J Med Chem. 2022 Jun 9;239:114525. doi: 10.1016/j.ejmech.2022.114525. Online ahead of print.ABSTRACTAzoles are a famous and promising class of drugs for treatment of a range of ailments especially fungal infections. A wide variety of azole derivatives are also known to exhibit tyrosinase inhibition, some of which possess promising activity with potential for treatment of dermatological disorders such as post-inflammatory hyperpigmentation, nevus, flecks, melasma, and melanoma. Recently, thiazolyl-resorcinol derivatives have demonstrated potent human tyrosinase inhibition with a safe and effective therapeutic profile fo...
Source: European Journal of Medicinal Chemistry - June 19, 2022 Category: Chemistry Authors: Usman Ghani Source Type: research

A comprehensive review on acridone based derivatives as future anti-cancer agents and their structure activity relationships
Eur J Med Chem. 2022 Jun 10;239:114527. doi: 10.1016/j.ejmech.2022.114527. Online ahead of print.ABSTRACTThe development of drug resistance and severe side-effects has reduced the clinical efficacy of the existing anti-cancer drugs available in the market. Thus, there is always a constant need to develop newer anti-cancer drugs with minimal adverse effects. Researchers all over the world have been focusing on various alternative strategies to discover novel, potent, and target specific molecules for cancer therapy. In this direction, several heterocyclic compounds are being explored but amongst them one promising heterocyc...
Source: European Journal of Medicinal Chemistry - June 19, 2022 Category: Chemistry Authors: Tanuja T Yadav Manikanta Murahari G J Peters Mayur Yc Source Type: research

Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase
Eur J Med Chem. 2022 Jun 13;239:114528. doi: 10.1016/j.ejmech.2022.114528. Online ahead of print.ABSTRACTNuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC50 values of 1.43 and 0.94 μM in NCI-H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and ...
Source: European Journal of Medicinal Chemistry - June 19, 2022 Category: Chemistry Authors: Yaoliang Sun Ying Zhang Xiaoai Chen Aisong Yu Wenhao Du Yuting Huang Feifei Wu Lei Yu Jiayi Li Cuiyun Wen Hong Yang Qiongyu Shi Meiyu Geng Xun Huang Shilin Xu Source Type: research

Azole inhibitors of mushroom and human tyrosinases: Current advances and prospects of drug development for melanogenic dermatological disorders
Eur J Med Chem. 2022 Jun 9;239:114525. doi: 10.1016/j.ejmech.2022.114525. Online ahead of print.ABSTRACTAzoles are a famous and promising class of drugs for treatment of a range of ailments especially fungal infections. A wide variety of azole derivatives are also known to exhibit tyrosinase inhibition, some of which possess promising activity with potential for treatment of dermatological disorders such as post-inflammatory hyperpigmentation, nevus, flecks, melasma, and melanoma. Recently, thiazolyl-resorcinol derivatives have demonstrated potent human tyrosinase inhibition with a safe and effective therapeutic profile fo...
Source: European Journal of Medicinal Chemistry - June 19, 2022 Category: Chemistry Authors: Usman Ghani Source Type: research