Design, synthesis and neurite outgrowth activity of novel ganglioside GM1 derivatives by remodeling of the fatty acid moiety
Eur J Med Chem. 2022 Aug 1;241:114636. doi: 10.1016/j.ejmech.2022.114636. Online ahead of print.ABSTRACTGanglioside GM1 is a glycosphingolipid found on mammalian cell membranes, and it is involved in ischemic encephalopathy, spinal cord injury and neurodegenerative diseases. Fatty acids, as a structure module of GM1, have been reported to affect its physiological function and neurite growth activity. Due to the limitation of preparation methods, the function of GM1 derivatives containing different fatty acids in nerve cells has not been systematically studied. To discover novel GM1 derivatives as nerve growth-promoting age...
Source: European Journal of Medicinal Chemistry - August 11, 2022 Category: Chemistry Authors: Xiaohui Chen Xuefeng Jin Fengtao Huang Juntao Wang Xuefeng Cao Peng George Wang Yan Feng Faqin Jiang Guangyu Yang Source Type: research

Intelligent triggering of nanomicelles based on a ROS-activated anticancer prodrug and photodynamic therapy (PDT)-synergistic therapy for lung cancers
This study aimed to design and synthesize a novel prodrug (DHA-S-CA) using a reactive oxygen species (ROS)-responsive moiety, thioacetal, to bridge cinnamaldehyde (CA) and dihydroartemisinin (DHA). As ROS are highly expressed in tumor tissues, the design uses the ROS-responsive moiety as an effective target for the nanodrug delivery system. Furthermore, the near-infrared dye IR808 and the prodrug were adopted to prepare co-loaded Soluplus®/TPGS nanomicelles (IR808/DHA-S-CA NMs). The photosensitized agent IR808 exhibited both tumor accumulation and cancer imaging properties while generating ROS during laser irradiation. In...
Source: European Journal of Medicinal Chemistry - August 11, 2022 Category: Chemistry Authors: Lixue Chen Ruping Xu Yanfang Ding Changyuan Wang Sitong Zhang Zhenya Sun Yali Chen Yunfeng Mi Meng Gao Xiaodong Ma Lei Li Source Type: research

4,6-Disubstituted-1H-Indazole-4-Amine derivatives with immune-chemotherapy effect and in vivo antitumor activity
Eur J Med Chem. 2022 Aug 6;241:114625. doi: 10.1016/j.ejmech.2022.114625. Online ahead of print.ABSTRACTTryptophan-2,3-dioxygenase (TDO) and indoleamine-2, 3-dioxygenase 1 (IDO1) are the important tumor immune checkpoints and TDO and IDO1 inhibition may present a potential approach to activate the T cell-mediated antitumor immune response during cancer treatment. Herein, we designed and synthesized a series of nitro-aryl 1H-indazole derivatives. SARs analysis showed that the nitro-aryl at the C-4 position of 1H-indazole was beneficial for TDO inhibition and directly tumoricidal effect and the substituents at C-6 position o...
Source: European Journal of Medicinal Chemistry - August 11, 2022 Category: Chemistry Authors: Cui Huo Zongyuan Luo Xiangli Ning Xin Kang Qin Yan Yuying Guo Guobo Li Zhouyu Wang Yuzhi Li Shan Qian Source Type: research

Design, synthesis and neurite outgrowth activity of novel ganglioside GM1 derivatives by remodeling of the fatty acid moiety
Eur J Med Chem. 2022 Aug 1;241:114636. doi: 10.1016/j.ejmech.2022.114636. Online ahead of print.ABSTRACTGanglioside GM1 is a glycosphingolipid found on mammalian cell membranes, and it is involved in ischemic encephalopathy, spinal cord injury and neurodegenerative diseases. Fatty acids, as a structure module of GM1, have been reported to affect its physiological function and neurite growth activity. Due to the limitation of preparation methods, the function of GM1 derivatives containing different fatty acids in nerve cells has not been systematically studied. To discover novel GM1 derivatives as nerve growth-promoting age...
Source: European Journal of Medicinal Chemistry - August 11, 2022 Category: Chemistry Authors: Xiaohui Chen Xuefeng Jin Fengtao Huang Juntao Wang Xuefeng Cao Peng George Wang Yan Feng Faqin Jiang Guangyu Yang Source Type: research

Intelligent triggering of nanomicelles based on a ROS-activated anticancer prodrug and photodynamic therapy (PDT)-synergistic therapy for lung cancers
This study aimed to design and synthesize a novel prodrug (DHA-S-CA) using a reactive oxygen species (ROS)-responsive moiety, thioacetal, to bridge cinnamaldehyde (CA) and dihydroartemisinin (DHA). As ROS are highly expressed in tumor tissues, the design uses the ROS-responsive moiety as an effective target for the nanodrug delivery system. Furthermore, the near-infrared dye IR808 and the prodrug were adopted to prepare co-loaded Soluplus®/TPGS nanomicelles (IR808/DHA-S-CA NMs). The photosensitized agent IR808 exhibited both tumor accumulation and cancer imaging properties while generating ROS during laser irradiation. In...
Source: European Journal of Medicinal Chemistry - August 11, 2022 Category: Chemistry Authors: Lixue Chen Ruping Xu Yanfang Ding Changyuan Wang Sitong Zhang Zhenya Sun Yali Chen Yunfeng Mi Meng Gao Xiaodong Ma Lei Li Source Type: research

Updated chemical scaffolds of ABCG2 inhibitors and their structure-inhibition relationships for future development
Eur J Med Chem. 2022 Jul 31;241:114628. doi: 10.1016/j.ejmech.2022.114628. Online ahead of print.ABSTRACTATP-binding cassette (ABC) transporters are pivotal for cell detoxification and survival. Overexpression of ABC transporter in tumor cells lead to chemoresistance through the efflux of chemotherapeutic agents. P-glycoprotein (Pgp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) are the major ABC transporters involved in multidrug resistance (MDR) of cancer cells against anticancer drugs. ABCG2 is one of the major transporters involved in the efflux of different cytoto...
Source: European Journal of Medicinal Chemistry - August 9, 2022 Category: Chemistry Authors: Md Moinul Sk Abdul Amin Tarun Jha Shovanlal Gayen Source Type: research

Updated chemical scaffolds of ABCG2 inhibitors and their structure-inhibition relationships for future development
Eur J Med Chem. 2022 Jul 31;241:114628. doi: 10.1016/j.ejmech.2022.114628. Online ahead of print.ABSTRACTATP-binding cassette (ABC) transporters are pivotal for cell detoxification and survival. Overexpression of ABC transporter in tumor cells lead to chemoresistance through the efflux of chemotherapeutic agents. P-glycoprotein (Pgp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) are the major ABC transporters involved in multidrug resistance (MDR) of cancer cells against anticancer drugs. ABCG2 is one of the major transporters involved in the efflux of different cytoto...
Source: European Journal of Medicinal Chemistry - August 9, 2022 Category: Chemistry Authors: Md Moinul Sk Abdul Amin Tarun Jha Shovanlal Gayen Source Type: research

Recent research and development of inhibitors targeting sentrin-specific protease 1 for the treatment of cancers
Eur J Med Chem. 2022 Aug 1;241:114650. doi: 10.1016/j.ejmech.2022.114650. Online ahead of print.ABSTRACTSmall ubiquitin-like modifier (SUMO)/sentrin-specific protease 1 (SENP1), is a cysteine protease that promotes SUMO maturation and deSUMOylation of target proteins and regulates transcription factors or co-regulatory factors to mediate gene transcription. Many studies have shown that SENP1 is the driving factor for a multitude of cancers including prostate cancer, liver cancer, and breast cancer. Inhibition of SENP1 activity has been proved to inhibit the survival, proliferation, invasion, and migration of cancer cells, ...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Junxia Wei Huijing Wang Qinwen Zheng Jifa Zhang Zhichao Chen Jiaxing Wang Liang Ouyang Yuxi Wang Source Type: research

Design, synthesis, and biological evaluation of pyrrolopyrimidine derivatives as novel Bruton's tyrosine kinase (BTK) inhibitors
Eur J Med Chem. 2022 Jul 15;241:114611. doi: 10.1016/j.ejmech.2022.114611. Online ahead of print.ABSTRACTDeveloping Bruton's tyrosine kinase (BTK) inhibitors has become a significant focus in recent years because BTK inhibition is an effective approach for the treatment of B-cell malignancies. For covalent BTK inhibitors, low oral bioavailability and low kinase selectivity remain unaddressed issues; thus, more diverse inhibitors with both novel structures and selective on target binding profiles are still needed. Here, four key regions where inhibitors bind to BTK were identified by analyzing the existing crystal structure...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Minjian Yang Huimin Jiang Zhuo Yang Xue Liu Hanyu Sun Mengyao Hao Jinping Hu Xiaoguang Chen Jing Jin Xiaojian Wang Source Type: research

Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents
Eur J Med Chem. 2022 Jul 16;241:114614. doi: 10.1016/j.ejmech.2022.114614. Online ahead of print.ABSTRACTMicrotubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments. Here, we sought to capitalize on this study with the aim to demonstrate that low affinity tubulin-bin...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Noelia Montel de la Roche Tobias M ühlethaler Rita Maria Concetta Di Martino Jose Antonio Ortega Dario Gioia Bibhas Roy Andrea E Prota Michel O Steinmetz Andrea Cavalli Source Type: research

Design, synthesis and antitumor evaluation of ATP dual-mimic 2,4-diarylaminopyrimidine and aminoindazole conjugates as potent anaplastic lymphoma kinase inhibitors
Eur J Med Chem. 2022 Jul 31;241:114626. doi: 10.1016/j.ejmech.2022.114626. Online ahead of print.ABSTRACTA series of hybrid anaplastic lymphoma kinase (ALK) inhibitors (Y1∼Y30) were designed by assembling aminoindazole of Entrectinib onto 2-position of 2,4-diarylaminopyrimidine (DAAP) fragment to serve as ATP dual-mimic agents. Under structure-based optimization, all conjugates were detected moderate to excellent cytotoxicity potency, among which the pyrrolidine analog Y28 exerted optimal antiproliferative effects on ALK-addicted cell lines with IC50 values below 20 nM. As a highly potent ALK inhibitor (ALKWT, IC50 = 1.6...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Jing Yang Deyi Ma Shuyu Liu Zehui Tan Ming Guo Zhi Cao Jiahao Zhang Xin Zhai Source Type: research

Discovery of 2,5-diphenyl-1,3,4-thiadiazole derivatives as HDAC inhibitors with DNA binding affinity
Eur J Med Chem. 2022 Jul 31;241:114634. doi: 10.1016/j.ejmech.2022.114634. Online ahead of print.ABSTRACTIncorporating a DNA-binding fragment in HDAC inhibitors has been proved to be an effective strategy for the treatment of hematologic malignancies by our group. However, similar to other approved HDAC inhibitors, their effects on solid tumor were poor. For this issue, a series of 2,5-diphenyl-1,3,4-thiadiazole hydroxamate derivatives were designed and synthesized as the HDAC inhibitors with DNA binding affinity. Among the target compounds, 4j not only bound with DNA effectively but also exhibited the most potent inhibito...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Chen Chen Hongrui Chu Anyang Wang Huanhuan Yin Yanqiao Gao Shuhua Liu Wei Li Leiqiang Han Source Type: research

A phthalocyanine-based photosensitizer for effectively combating triple negative breast cancer with enhanced photodynamic anticancer activity and immune response
Eur J Med Chem. 2022 Aug 1;241:114644. doi: 10.1016/j.ejmech.2022.114644. Online ahead of print.ABSTRACTAlthough photodynamic therapy (PDT) has attracted great interest, the photosensitizers in clinical had weak inhibition on metastasis and invasion of cancers. Additionally the immune response induced by PDT was insufficient to eradicate cancer. Herein, indoximod, an inhibitor of indoleamine 2,3-dioxygenase (IDO), is introduced to concatenate with zinc phthalocyanines (ZnPc) for effectively overcoming above inadequacy. Due to indoximod moiety, photosensitizer 1-MT-Pc can obtain enhanced intracellular uptake and high reacti...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Kunshan Huang Meiqi Yan Han Zhang Jinping Xue Juanjuan Chen Source Type: research

Recent research and development of inhibitors targeting sentrin-specific protease 1 for the treatment of cancers
Eur J Med Chem. 2022 Aug 1;241:114650. doi: 10.1016/j.ejmech.2022.114650. Online ahead of print.ABSTRACTSmall ubiquitin-like modifier (SUMO)/sentrin-specific protease 1 (SENP1), is a cysteine protease that promotes SUMO maturation and deSUMOylation of target proteins and regulates transcription factors or co-regulatory factors to mediate gene transcription. Many studies have shown that SENP1 is the driving factor for a multitude of cancers including prostate cancer, liver cancer, and breast cancer. Inhibition of SENP1 activity has been proved to inhibit the survival, proliferation, invasion, and migration of cancer cells, ...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Junxia Wei Huijing Wang Qinwen Zheng Jifa Zhang Zhichao Chen Jiaxing Wang Liang Ouyang Yuxi Wang Source Type: research

Design, synthesis, and biological evaluation of pyrrolopyrimidine derivatives as novel Bruton's tyrosine kinase (BTK) inhibitors
Eur J Med Chem. 2022 Jul 15;241:114611. doi: 10.1016/j.ejmech.2022.114611. Online ahead of print.ABSTRACTDeveloping Bruton's tyrosine kinase (BTK) inhibitors has become a significant focus in recent years because BTK inhibition is an effective approach for the treatment of B-cell malignancies. For covalent BTK inhibitors, low oral bioavailability and low kinase selectivity remain unaddressed issues; thus, more diverse inhibitors with both novel structures and selective on target binding profiles are still needed. Here, four key regions where inhibitors bind to BTK were identified by analyzing the existing crystal structure...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Minjian Yang Huimin Jiang Zhuo Yang Xue Liu Hanyu Sun Mengyao Hao Jinping Hu Xiaoguang Chen Jing Jin Xiaojian Wang Source Type: research