Discovery of quinazoline derivatives CZw-124 as a pan-TRK inhibitor with potent anticancer effects in vitro and in vivo
Eur J Med Chem. 2022 May 11;238:114451. doi: 10.1016/j.ejmech.2022.114451. Online ahead of print.ABSTRACTHerein, we report the discovery process and antitumor activity of the TRK inhibitor CZw-124 (8o), which is a quinazoline derivative. Starting from a PAK4 inhibitor, we used various drug design strategies, including pharmacophore feature supplementation, F-scanning, and blocking metabolic sites, and finally found a TRK inhibitor CZw-124 that is effective in vitro and in vivo. Docking studies and molecular dynamics simulations revealed a possible mode of binding of CZw-124 to TRKA. Biological activity evaluation showed th...
Source: European Journal of Medicinal Chemistry - May 26, 2022 Category: Chemistry Authors: Tianxiao Wu Qiaohua Qin Ruicheng Lv Nian Liu Wenbo Yin Chenzhou Hao Yin Sun Chu Zhang Yixiang Sun Dongmei Zhao Maosheng Cheng Source Type: research

Design, synthesis of novel triptolide-glucose conjugates targeting glucose Transporter-1 and their selective antitumor effect
Eur J Med Chem. 2022 May 17;238:114463. doi: 10.1016/j.ejmech.2022.114463. Online ahead of print.ABSTRACTSix positional isomers of triptolide-glucose conjugates (TG1α, TG1β, TG2, TG3, TG4 and TG6) were designed and synthesized. These conjugates exhibited better water solubility, and had selective cytotoxicity between tumor cells with high expression of glucose transport-1 (Glut-1) and non-tumor cells with low expression of Glut-1, in which TG2 formed by triptolide (TPL) and d-glucose C2-OH had the strongest cytotoxicity to tumor cells and lowest toxicity in non-tumor cells, therefore the highest relative therapeutic inde...
Source: European Journal of Medicinal Chemistry - May 26, 2022 Category: Chemistry Authors: Yan Liu Jiaqing Huang Min Wu Bi Liu Qiaofa Lin Jingjing Wu Yuhua Ouyang Xin Guo Ruyi Huang Yongmin Zhang Jianhua Xu Source Type: research

From tryptophan to novel mitochondria-disruptive agent, synthesis and biological evaluation of 1,2,3,6-tetrasubstituted carbazoles
Eur J Med Chem. 2022 May 13;238:114453. doi: 10.1016/j.ejmech.2022.114453. Online ahead of print.ABSTRACTMitochondrial targeting plays an important role in anticancer therapy. The Mn(III)-promoted cyclization of 5-(1H-indol-3-yl)-3-oxopentanoic acid allow to obtain novel substituted carbazole derivatives that can act as mitochondria-disruptive agents. The starting materials used for the synthesis of these new aminocarbazoles are oxopentanoate derivatives of tryptophan. The scope and limitation of this method of synthesis are determined by a series of experiments. The prepared carbazole derivatives are screened for their in...
Source: European Journal of Medicinal Chemistry - May 24, 2022 Category: Chemistry Authors: Milena Witkowska Natalia Maciejewska Ma łgorzata Ryczkowska Mateusz Olszewski Maciej Bagi ński S ławomir Makowiec Source Type: research

From tryptophan to novel mitochondria-disruptive agent, synthesis and biological evaluation of 1,2,3,6-tetrasubstituted carbazoles
Eur J Med Chem. 2022 May 13;238:114453. doi: 10.1016/j.ejmech.2022.114453. Online ahead of print.ABSTRACTMitochondrial targeting plays an important role in anticancer therapy. The Mn(III)-promoted cyclization of 5-(1H-indol-3-yl)-3-oxopentanoic acid allow to obtain novel substituted carbazole derivatives that can act as mitochondria-disruptive agents. The starting materials used for the synthesis of these new aminocarbazoles are oxopentanoate derivatives of tryptophan. The scope and limitation of this method of synthesis are determined by a series of experiments. The prepared carbazole derivatives are screened for their in...
Source: European Journal of Medicinal Chemistry - May 24, 2022 Category: Chemistry Authors: Milena Witkowska Natalia Maciejewska Ma łgorzata Ryczkowska Mateusz Olszewski Maciej Bagi ński S ławomir Makowiec Source Type: research

Design, synthesis, and in vitro protective effect evaluation of α-carboline derivatives against H < sub > 2 < /sub > O < sub > 2 < /sub > -induced cardiomyocyte injury
Eur J Med Chem. 2022 May 19;238:114469. doi: 10.1016/j.ejmech.2022.114469. Online ahead of print.ABSTRACTAs one of the most important features of myocardial ischemia reperfusion (MI/R) injury, the overproduction of reactive oxygen species (ROS) overwhelms the intrinsic antioxidant and impairs the function of mitochondria and, finally, leads to cardiomyocyte death. To improve the damage of cardiomyocyte caused by oxidative stress, a series of α-carboline derivatives were designed and synthesized in this study. The biological studies revealed that most of the α-carbolines exhibited obvious protective activities against H2O...
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Rong-Hong Zhang Dan Yang Xiang-Ming Liao Hong Zhang Guo-Qi Chen Wen-Li Zhang Yu-Chan Wang Cong Wang Shang-Gao Liao Meng Zhou Yong-Lin Wang Yong-Jun Li Source Type: research

Glycosylation increases the anti-QS as well as anti-biofilm and anti-adhesion ability of the cyclo (L-Trp-L-Ser) against Pseudomonas aeruginosa
Eur J Med Chem. 2022 May 13;238:114457. doi: 10.1016/j.ejmech.2022.114457. Online ahead of print.ABSTRACTPseudomonas aeruginosa infections pose a huge threat to cystic fibrosis patients, as well as those suffering from immunodeficiency. Antimicrobial resistance, especially multi-drug resistance, due to its ability to aggregate the compact biofilm, makes it more inefficient to treat this pathogen with traditional antibiotics. Biofilm and quorum sensing (QS) have become the alternative targets for treating P. aeruginosa infections. Previously, a cyclic dipeptide cyclo(L-Trp-L-Ser) has been identified as a QS inhibitor of P. ...
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Yinglu Wang Lile Pan Li Li Ruipin Cao Qian Zheng Zuxian Xu Chang-Jer Wu Hu Zhu Source Type: research

Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies
Eur J Med Chem. 2022 May 16;238:114461. doi: 10.1016/j.ejmech.2022.114461. Online ahead of print.ABSTRACTCyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administrat...
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Xinren Wang Xiaoyue Liu Jianhang Huang Chenhe Liu Hongmei Li Cong Wang Qianqian Hong Yan Lei Jiawei Xia Ziheng Yu Ruinan Dong Junyu Xu Zhenlin Tu ChunQi Duan Shuwen Li Tao Lu Weifang Tang Yadong Chen Source Type: research

Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities
In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent.PMID:35605363 | DOI:10.1016/j.ejmech.2022.114467 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Jian Song Yong-Feng Guan Wen-Bo Liu Chun-Hong Song Xin-Yi Tian Ting Zhu Xiang-Jing Fu Ying-Qiu Qi Sai-Yang Zhang Source Type: research

Design, synthesis, and in vitro protective effect evaluation of α-carboline derivatives against H < sub > 2 < /sub > O < sub > 2 < /sub > -induced cardiomyocyte injury
Eur J Med Chem. 2022 May 19;238:114469. doi: 10.1016/j.ejmech.2022.114469. Online ahead of print.ABSTRACTAs one of the most important features of myocardial ischemia reperfusion (MI/R) injury, the overproduction of reactive oxygen species (ROS) overwhelms the intrinsic antioxidant and impairs the function of mitochondria and, finally, leads to cardiomyocyte death. To improve the damage of cardiomyocyte caused by oxidative stress, a series of α-carboline derivatives were designed and synthesized in this study. The biological studies revealed that most of the α-carbolines exhibited obvious protective activities against H2O...
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Rong-Hong Zhang Dan Yang Xiang-Ming Liao Hong Zhang Guo-Qi Chen Wen-Li Zhang Yu-Chan Wang Cong Wang Shang-Gao Liao Meng Zhou Yong-Lin Wang Yong-Jun Li Source Type: research

Glycosylation increases the anti-QS as well as anti-biofilm and anti-adhesion ability of the cyclo (L-Trp-L-Ser) against Pseudomonas aeruginosa
Eur J Med Chem. 2022 May 13;238:114457. doi: 10.1016/j.ejmech.2022.114457. Online ahead of print.ABSTRACTPseudomonas aeruginosa infections pose a huge threat to cystic fibrosis patients, as well as those suffering from immunodeficiency. Antimicrobial resistance, especially multi-drug resistance, due to its ability to aggregate the compact biofilm, makes it more inefficient to treat this pathogen with traditional antibiotics. Biofilm and quorum sensing (QS) have become the alternative targets for treating P. aeruginosa infections. Previously, a cyclic dipeptide cyclo(L-Trp-L-Ser) has been identified as a QS inhibitor of P. ...
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Yinglu Wang Lile Pan Li Li Ruipin Cao Qian Zheng Zuxian Xu Chang-Jer Wu Hu Zhu Source Type: research

Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies
Eur J Med Chem. 2022 May 16;238:114461. doi: 10.1016/j.ejmech.2022.114461. Online ahead of print.ABSTRACTCyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administrat...
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Xinren Wang Xiaoyue Liu Jianhang Huang Chenhe Liu Hongmei Li Cong Wang Qianqian Hong Yan Lei Jiawei Xia Ziheng Yu Ruinan Dong Junyu Xu Zhenlin Tu ChunQi Duan Shuwen Li Tao Lu Weifang Tang Yadong Chen Source Type: research

Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities
In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent.PMID:35605363 | DOI:10.1016/j.ejmech.2022.114467 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 23, 2022 Category: Chemistry Authors: Jian Song Yong-Feng Guan Wen-Bo Liu Chun-Hong Song Xin-Yi Tian Ting Zhu Xiang-Jing Fu Ying-Qiu Qi Sai-Yang Zhang Source Type: research

New TRPM8 blockers exert anticancer activity over castration-resistant prostate cancer models
Eur J Med Chem. 2022 May 12;238:114435. doi: 10.1016/j.ejmech.2022.114435. Online ahead of print.ABSTRACTTRPM8 has recently emerged as a druggable target in prostate cancer (PC) and TRPM8 modulators have been proposed as potential anticancer agents in this pathology. We have recently demonstrated their effectiveness in a castration-resistant prostate cancer (CRPC) model that is usually resistant to androgen deprivation therapy (ADT) and is considered the most aggressive form of PC. This is why the discovery of selective, effective, and potent TRPM8 modulators would improve the molecular arsenal in support of PC standard-of...
Source: European Journal of Medicinal Chemistry - May 22, 2022 Category: Chemistry Authors: Veronica Di Sarno Pia Giovannelli Alicia Medina-Peris Tania Ciaglia Marzia Di Donato Simona Musella Gianluigi Lauro Vincenzo Vestuto Gerardina Smaldone Francesca Di Matteo Giuseppe Bifulco Gabriella Castoria Antimo Migliaccio Asia Fernandez-Carvajal Pietr Source Type: research

Synthesis of 10,10'-bis(trifluoromethyl) marinopyrrole A derivatives and evaluation of their antiviral activities in vitro
Eur J Med Chem. 2022 May 6;238:114436. doi: 10.1016/j.ejmech.2022.114436. Online ahead of print.ABSTRACTFlavivirus and enterovirus can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases or even death. Since effective vaccine is currently unavailable against most of these deadly viruses, antiviral chemical drugs remain in urgent need. To meet this unmet demand, we developed a series of 10,10'-bis(trifluoromethyl) marinopyrrole A derivates bearing various substituents at C5'-positions, which exhibited impressive in vitro activities against flaviviruses (ZIKV, DENV, YFV, JEV) and ente...
Source: European Journal of Medicinal Chemistry - May 22, 2022 Category: Chemistry Authors: Yaxin Xiao Jingjing Yang Liangjing Zou Pingzhou Wu Wei Li Yunzheng Yan Yuexiang Li Song Li Hao Song Wu Zhong Yong Qin Source Type: research

New TRPM8 blockers exert anticancer activity over castration-resistant prostate cancer models
Eur J Med Chem. 2022 May 12;238:114435. doi: 10.1016/j.ejmech.2022.114435. Online ahead of print.ABSTRACTTRPM8 has recently emerged as a druggable target in prostate cancer (PC) and TRPM8 modulators have been proposed as potential anticancer agents in this pathology. We have recently demonstrated their effectiveness in a castration-resistant prostate cancer (CRPC) model that is usually resistant to androgen deprivation therapy (ADT) and is considered the most aggressive form of PC. This is why the discovery of selective, effective, and potent TRPM8 modulators would improve the molecular arsenal in support of PC standard-of...
Source: European Journal of Medicinal Chemistry - May 22, 2022 Category: Chemistry Authors: Veronica Di Sarno Pia Giovannelli Alicia Medina-Peris Tania Ciaglia Marzia Di Donato Simona Musella Gianluigi Lauro Vincenzo Vestuto Gerardina Smaldone Francesca Di Matteo Giuseppe Bifulco Gabriella Castoria Antimo Migliaccio Asia Fernandez-Carvajal Pietr Source Type: research