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Lu T, Zhang Y, Li J, Dai M, Liu H, Zhu H, Fu S, Dong X, Sun F, Lin H, Zhang X, Yang W, Yu P, Zou H. Indolizine Derivatives Inhibit TRPM2 and Protect against Ischemic Brain Injury with an Extended Treatment Window. J Med Chem 2025; 68:7642-7661. [PMID: 40168472 DOI: 10.1021/acs.jmedchem.5c00186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
Ischemic stroke, a major cause of disability and death worldwide, lacks effective treatments due to the complexity of brain ischemia/reperfusion (I/R) injury. The transient receptor potential melastatin 2 (TRPM2) channel is a promising therapeutic target. In this study, an extracellular TRPM2 inhibitor A1 with an indolizine scaffold was identified through chemical library screening. Four series of indolizine derivatives were synthesized, yielding four compounds with TRPM2 inhibitory activity comparable to or superior to A1, as confirmed by calcium fluorescence and electrophysiological assays. These compounds demonstrated significant neuroprotective effects in vitro. Among them, D10 showed robust efficacy in reducing cerebral infarction in a transient middle cerebral artery occlusion (tMCAO) model, surpassing edaravone. When administered 24 h postreperfusion and continued for 7 days, D10 exhibited sustained in vivo antistroke activity and improved survival rates compared to edaravone and vehicle controls. D10 represents a promising lead compound for ischemic stroke therapy.
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Affiliation(s)
- Tinghao Lu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Yi Zhang
- Zhejiang University School of Medicine, Hangzhou 310058, PR China
| | - Jinbiao Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - MeiJie Dai
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou 310058, PR China
| | - Huan Liu
- Zhejiang University School of Medicine, Hangzhou 310058, PR China
- Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, PR China
| | - Huajian Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Shaozi Fu
- Zhejiang University School of Medicine, Hangzhou 310058, PR China
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Xianhao Dong
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Fenghao Sun
- Zhongshan hospital, Fudan University, Shanghai 200000, PR China
| | - Hongwei Lin
- Zhejiang University School of Medicine, Hangzhou 310058, PR China
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Xiangnan Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
- Institute of Pharmacology and Toxicology, State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei Yang
- Zhejiang University School of Medicine, Hangzhou 310058, PR China
- Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, PR China
| | - Peilin Yu
- Zhejiang University School of Medicine, Hangzhou 310058, PR China
- Department of Toxicology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, PR China
| | - Hongbin Zou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
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2
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Chen S, Luo Y, Yu P, Yue X, Yang W. [Advances in the development of transient receptor potential melastatin 2 channel inhibitors]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2025; 54:120-130. [PMID: 39909465 PMCID: PMC11956857 DOI: 10.3724/zdxbyxb-2024-0586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/20/2024] [Indexed: 02/07/2025]
Abstract
Studies on specific transient receptor potential melastatin 2 (TRPM2) channel inhibitors can deepen our understanding of the pathological mechanism of related diseases, and allow discovery of novel, effective targets and drugs for therapy. The development of TRPM2 channel inhibitors can be broadly classified into four categories with distinct characteristics: reutilization and structural modification of homologous ion channel modulators to produce a diverse array of TRPM2 channel inhibitors with strong inhibitory effects; TRPM2 channel inhibitors based on channel gating mechanism with high specificity; inhibitors identified through high-throughput screening with novel chemical structures; inhibitors developed from natural antioxidants with higher safety. In recent years, the application of computer-aided drug design has significantly accelerated the development of TRPM2 channel inhibitors. Several promising compounds such as ZA18, A1 and D9 have been discovered, and it is expected that more potent and selective TRPM2 channel inhibitor scaffolds will be discovered in the future. This article reviews the advances on the studies of TRPM2 channel inhibitors, aiming to provide insights for further research and clinical application of TRPM2 channel inhibitors.
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Affiliation(s)
- Shiyao Chen
- Department of Biophysics, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Yanping Luo
- Department of Biophysics, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Peilin Yu
- Department of Toxicology, School of Public Health, Zhejiang University School of Medicine , Hangzhou 310058, China
| | - Xiaomin Yue
- Department of Biophysics, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Wei Yang
- Department of Biophysics, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
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3
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Chen Z, Vallega KA, Boda VK, Quan Z, Wang D, Fan S, Wang Q, Ramalingam SS, Li W, Sun S. Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2310126. [PMID: 39044361 PMCID: PMC11425210 DOI: 10.1002/advs.202310126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 06/30/2024] [Indexed: 07/25/2024]
Abstract
There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.
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Affiliation(s)
- Zhen Chen
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Karin A. Vallega
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Vijay K. Boda
- Department of Pharmaceutical SciencesCollege of PharmacyUniversity of Tennessee Health Science CenterMemphisTN38163USA
| | - Zihan Quan
- Department of PathologyThe Second Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Dongsheng Wang
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Songqing Fan
- Department of PathologyThe Second Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Qiming Wang
- Department of Internal MedicineThe Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhou450008P. R. China
| | - Suresh S. Ramalingam
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Wei Li
- Department of Pharmaceutical SciencesCollege of PharmacyUniversity of Tennessee Health Science CenterMemphisTN38163USA
| | - Shi‐Yong Sun
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
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Yuan Y, Zhang Q, Qiu F, Kang N, Zhang Q. Targeting TRPs in autophagy regulation and human diseases. Eur J Pharmacol 2024; 977:176681. [PMID: 38821165 DOI: 10.1016/j.ejphar.2024.176681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/06/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
Transient receptor potential channels (TRPs) are widely recognized as a group of ion channels involved in various sensory perceptions, such as temperature, taste, pressure, and vision. While macroautophagy (hereafter referred to as autophagy) is primarily regulated by core machinery, the ion exchange mediated by TRPs between intracellular and extracellular compartments, as well as within organelles and the cytoplasm, plays a crucial role in autophagy regulation as an important signaling transduction mechanism. Moreover, certain TRPs can directly interact with autophagy regulatory proteins to participate in autophagy regulation. In this article, we provide an in-depth review of the current understanding of the regulatory mechanisms of autophagy, with a specific focus on TRPs. Furthermore, we highlight the potential prospects for drug development targeting TRPs in autophagy for the treatment of human diseases.
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Affiliation(s)
- Yongkang Yuan
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Qiuju Zhang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Feng Qiu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
| | - Ning Kang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
| | - Qiang Zhang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
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Wei Y, Li M, Hu Y, Lu J, Wang L, Yin Q, Hong X, Tian J, Wang H. PCC0208057 as a small molecule inhibitor of TRPC6 in the treatment of prostate cancer. Front Pharmacol 2024; 15:1352373. [PMID: 38567350 PMCID: PMC10986179 DOI: 10.3389/fphar.2024.1352373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Prostate cancer (PCa) is a common malignant tumor, whose morbidity and mortality keep the top three in the male-related tumors in developed countries. Abnormal ion channels, such as transient receptor potential canonical 6 (TRPC6), are reported to be involved in the carcinogenesis and progress of prostate cancer and have become potential drug targets against prostate cancer. Here, we report a novel small molecule inhibitor of TRPC6, designated as PCC0208057, which can suppress the proliferation and migration of prostate cancer cells in vitro, and inhibit the formation of Human umbilical vein endothelial cells cell lumen. PCC0208057 can effectively inhibit the growth of xenograft tumor in vivo. Molecular mechanism studies revealed that PCC0208057 could directly bind and inhibit the activity of TRPC6, which then induces the prostate cancer cells arrested in G2/M phase via enhancing the phosphorylation of Nuclear Factor of Activated T Cells (NFAT) and Cdc2. Taken together, our study describes for the first time that PCC0208057, a novel TRPC6 inhibitor, might be a promising lead compound for treatment of prostate cancer.
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Affiliation(s)
- Yingjie Wei
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Min Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Yuemiao Hu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Jing Lu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Lin Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Qikun Yin
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Xuechuan Hong
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, China
| | - Jingwei Tian
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
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Chen C, Zhu T, Gong L, Hu Z, Wei H, Fan J, Lin D, Wang X, Xu J, Dong X, Wang Y, Xia N, Zeng L, Jiang P, Xie Y. Trpm2 deficiency in microglia attenuates neuroinflammation during epileptogenesis by upregulating autophagy via the AMPK/mTOR pathway. Neurobiol Dis 2023; 186:106273. [PMID: 37648036 DOI: 10.1016/j.nbd.2023.106273] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/15/2023] [Accepted: 08/27/2023] [Indexed: 09/01/2023] Open
Abstract
Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.
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Affiliation(s)
- Chen Chen
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Tao Zhu
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310030, China
| | - Lifen Gong
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Zhe Hu
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Hao Wei
- Department of Pharmacy, Xuzhou Medical University, 221004 Xuzhou, China
| | - Jianchen Fan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China
| | - Donghui Lin
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Xiaojun Wang
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Junyu Xu
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Xinyan Dong
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Yifan Wang
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Ningxiao Xia
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China
| | - Linghui Zeng
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China
| | - Peifang Jiang
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China.
| | - Yicheng Xie
- Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China.
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Mendogralo EY, Nesterova LY, Nasibullina ER, Shcherbakov RO, Tkachenko AG, Sidorov RY, Sukonnikov MA, Skvortsov DA, Uchuskin MG. The Synthesis and Biological Evaluation of 2-(1 H-Indol-3-yl)quinazolin-4(3 H)-One Derivatives. Molecules 2023; 28:5348. [PMID: 37513221 PMCID: PMC10384628 DOI: 10.3390/molecules28145348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/03/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
The treatment of many bacterial diseases remains a significant problem due to the increasing antibiotic resistance of their infectious agents. Among others, this is related to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA) and Mycobacterium tuberculosis. In the present article, we report on antibacterial compounds with activity against both S. aureus and MRSA. A straightforward approach to 2-(1H-indol-3-yl)quinazolin-4(3H)-one and their analogues was developed. Their structural and functional relationships were also considered. The antimicrobial activity of the synthesized compounds against Mycobacterium tuberculosis H37Rv, S. aureus ATCC 25923, MRSA ATCC 43300, Candida albicans ATCC 10231, and their role in the inhibition of the biofilm formation of S. aureus were reported. 2-(5-Iodo-1H-indol-3-yl)quinazolin-4(3H)-one (3k) showed a low minimum inhibitory concentration (MIC) of 0.98 μg/mL against MRSA. The synthesized compounds were assessed via molecular docking for their ability to bind long RSH (RelA/SpoT homolog) proteins using mycobacterial and streptococcal (p)ppGpp synthetase structures as models. The cytotoxic activity of some synthesized compounds was studied. Compounds 3c, f, g, k, r, and 3z displayed significant antiproliferative activities against all the cancer cell lines tested. Indolylquinazolinones 3b, 3e, and 3g showed a preferential suppression of the growth of rapidly dividing A549 cells compared to slower growing fibroblasts of non-tumor etiology.
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Affiliation(s)
- Elena Y Mendogralo
- Department of Chemistry, Perm State University, Bukireva St. 15, 614990 Perm, Russia
| | - Larisa Y Nesterova
- Department of Chemistry, Perm State University, Bukireva St. 15, 614990 Perm, Russia
- Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences, Goleva St. 13, 614081 Perm, Russia
| | | | - Roman O Shcherbakov
- Department of Chemistry, Perm State University, Bukireva St. 15, 614990 Perm, Russia
| | - Alexander G Tkachenko
- Department of Chemistry, Perm State University, Bukireva St. 15, 614990 Perm, Russia
- Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences, Goleva St. 13, 614081 Perm, Russia
| | - Roman Y Sidorov
- Department of Chemistry, Perm State University, Bukireva St. 15, 614990 Perm, Russia
- Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences, Goleva St. 13, 614081 Perm, Russia
| | - Maxim A Sukonnikov
- Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia
| | - Dmitry A Skvortsov
- Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia
| | - Maxim G Uchuskin
- Department of Chemistry, Perm State University, Bukireva St. 15, 614990 Perm, Russia
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Zhong C, Yang J, Zhang Y, Fan X, Fan Y, Hua N, Li D, Jin S, Li Y, Chen P, Chen Y, Cai X, Zhang Y, Jiang L, Yang W, Yu P, Lin H. TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca 2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression. RESEARCH (WASHINGTON, D.C.) 2023; 6:0159. [PMID: 37275121 PMCID: PMC10232356 DOI: 10.34133/research.0159] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 05/03/2023] [Indexed: 06/07/2023]
Abstract
Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.
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Affiliation(s)
- Cheng Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Jing Yang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yiyin Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yang Fan
- Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Ning Hua
- Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province,
Xinxiang Medical University, 453003 Xinxiang, Henan, P.R. China
| | - Duguang Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Peng Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yongle Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Xiaobo Cai
- Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
| | - Yi Zhang
- Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
| | - Linhua Jiang
- Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province,
Xinxiang Medical University, 453003 Xinxiang, Henan, P.R. China
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, UK
| | - Wei Yang
- Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
| | - Peilin Yu
- Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
- Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital,
School of Medicine, Zhejiang University, Hangzhou 310020, P.R. China
- College of Biomedical Engineering and Instrument Science,
Zhejiang University, Hangzhou 310058, P.R. China
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9
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[HDBU][HSO4]-catalyzed facile synthesis of new 1,2,3-triazole-tethered 2,3-dihydroquinazolin-4[1H]-one derivatives and their DPPH radical scavenging activity. RESEARCH ON CHEMICAL INTERMEDIATES 2022. [DOI: 10.1007/s11164-021-04639-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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10
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Zhong X, Lin S, Xu H, Zhao X, Gao H, Wei Y, Zhou Z. Rh(III)-Catalysed Cascade C-H Imidization/Cyclization of N-Methoxybenzamides with Isoxazolones for the Assembly of Dihydroquinazolin-4(1H)-one Derivatives. Org Chem Front 2022. [DOI: 10.1039/d1qo01935j] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
By virtue of isoxazolones as viable imidizating reagents, an efficient Rh(III)-catalysed redox-neutral C-H imidization/cyclization cascade has been developed for the specific assembly of dihydroquinazolin-4(1H)-ones with the equipment of a quaternary...
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11
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Zhao S, Zhang H, Jin H, Cai X, Zhang R, Jin Z, Yang W, Yu P, Zhang L, Liu Z. Design, synthesis and biological activities of benzo[d]imidazo[1,2-a]imidazole derivatives as TRPM2-specfic inhibitors. Eur J Med Chem 2021; 225:113750. [PMID: 34416664 DOI: 10.1016/j.ejmech.2021.113750] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/26/2021] [Accepted: 08/04/2021] [Indexed: 10/20/2022]
Abstract
Transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer and neurodegenerative diseases. However, the lack of specific inhibitors impedes the development of TRPM2 targeted therapeutic agents. To develop a selective TRPM2 inhibitor, three-dimensional similarity-based screening strategy was employed using the energy-minimized conformation of non-selective TRPM2 inhibitor 2-APB as the query structure, which resulted in the discovery of a novel tricyclic TRPM2 inhibitor Z-4 with benzo[d]imidazo[1,2-a]imidazole skeleton. A series of Z-4 derivatives were subsequently synthesized and evaluated using calcium imaging and electrophysiology approaches. Among them, preferred compounds ZA10 and ZA18 inhibited the TRPM2 channel with micromolar half-maximal inhibitory concentration values and exhibited TRPM2 selectivity over the TRPM8 channel, TRPV1 channel, InsP3 receptor and Orai channel. The analysis of structure-activity relationship provides valuable insights for further development of selective TRPM2 inhibitors. Neuroprotection assay showed that ZA10 and ZA18 could effectively reduce the mortality of SH-SY5Y cells induced by H2O2. These findings enrich the structure types of existing TRPM2 inhibitors and might provide a new tool for the study of TRPM2 function in Reactive oxygen species (ROS) -related diseases.
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Affiliation(s)
- Siqi Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Han Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Hongwei Jin
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Xiaobo Cai
- Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, PR China
| | - Rongxue Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Zefang Jin
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Wei Yang
- Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, PR China
| | - Peilin Yu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
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12
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Wang Q, Liu N, Ni YS, Yang JM, Ma L, Lan XB, Wu J, Niu JG, Yu JQ. TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention. Channels (Austin) 2021; 15:136-154. [PMID: 33455532 PMCID: PMC7833771 DOI: 10.1080/19336950.2020.1870088] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 01/14/2023] Open
Abstract
Ischemic stroke has a high lethality rate worldwide, and novel treatments are limited. Calcium overload is considered to be one of the mechanisms of cerebral ischemia. Transient receptor potential melastatin 2 (TRPM2) is a reactive oxygen species (ROS)-sensitive calcium channel. Cerebral ischemia-induced TRPM2 activation triggers abnormal intracellular Ca2+ accumulation and cell death, which in turn causes irreversible brain damage. Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. This review provides data on the expression, structure, and function of TRPM2 and illustrates its cellular and molecular mechanisms in ischemic stroke. Natural and synthetic TRPM2 inhibitors (both specific and nonspecific) are also summarized. The three-dimensional protein structure of TRPM2 has been identified, and we speculate that molecular simulation techniques will be essential for developing new drugs that block TRPM2 channels. These insights about TRPM2 may be the key to find potent therapeutic approaches for the treatment of ischemic stroke.
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Affiliation(s)
- Qing Wang
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Ning Liu
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Yuan-Shu Ni
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Jia-Mei Yang
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Lin Ma
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China
| | - Xiao-Bing Lan
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Jing Wu
- Laboratory Animal Center, Ningxia Medical University, Yinchuan, China
| | - Jian-Guo Niu
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China
| | - Jian-Qiang Yu
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
- Ningxia Collaborative Innovation Center of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
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13
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TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species. Antioxidants (Basel) 2021; 10:antiox10081243. [PMID: 34439491 PMCID: PMC8389341 DOI: 10.3390/antiox10081243] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022] Open
Abstract
TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia–reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other “natural” compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury.
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14
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Anti-TB evaluation of novel 2,3-dihydroquinazolin-4(1H)-ones and in silico studies of the active compounds. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02733-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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15
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Zhang H, Yu P, Lin H, Jin Z, Zhao S, Zhang Y, Xu Q, Jin H, Liu Z, Yang W, Zhang L. The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both In Vitro and In Vivo. J Med Chem 2021; 64:3976-3996. [PMID: 33784097 DOI: 10.1021/acs.jmedchem.0c02129] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer, and neurodegenerative diseases. However, the limit of specific inhibitors impedes the development of TRPM2-targeted therapeutic agents. To discover more potent and selective TRPM2 inhibitors, 59 N-(p-amylcinnamoyl) anthranilic acid (ACA) derivatives were synthesized and evaluated using calcium imaging and electrophysiology approaches. Systematic structure-activity relationship studies resulted in some potent compounds inhibiting the TRPM2 channel with sub-micromolar half-maximal inhibitory concentration values. Among them, the preferred compound A23 exhibited TRPM2 selectivity over TRPM8 and TRPV1 channels as well as phospholipase A2 and showed neuroprotective activity in vitro. Following pharmacokinetic studies, A23 was further evaluated in a transient middle cerebral artery occlusion model in vivo, which significantly reduced cerebral infarction. These data indicate that A23 might serve as a useful tool for TRPM2-related research as well as a lead compound for the development of therapeutic agents for ischemic injury.
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Affiliation(s)
- Han Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Peilin Yu
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, P. R. China
| | - Hongwei Lin
- Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P. R. China
| | - Zefang Jin
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Siqi Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Yi Zhang
- Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P. R. China
| | - Qingxia Xu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Hongwei Jin
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Wei Yang
- Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P. R. China
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
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16
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Wei Y, Zhang M, Lyu Z, Yang G, Tian T, Ding M, Zeng X, Xu F, Wang P, Li F, Liu Y, Cao Z, Lu J, Hong X, Wang H. Benzothiazole Amides as TRPC3/6 Inhibitors for Gastric Cancer Treatment. ACS OMEGA 2021; 6:9196-9203. [PMID: 33842788 PMCID: PMC8028158 DOI: 10.1021/acsomega.1c00514] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/16/2021] [Indexed: 06/12/2023]
Abstract
Transient receptor potential canonical channel 6 (TRPC6) has been implicated in many kinds of malignant tumors, but very few potent TRPC6 antagonists are available. In this study, a benzothiazole amide derivative 1a was discovered as a TRPC6 activator in a cell-based high-throughput screening. A series of benzothiazole amide derivatives were designed and synthesized. The docking analyses indicated that the conformations of the compounds bound to TRPC6 determined the agonistic or antagonistic activity of the compounds against TRPC6, and compound 1s with the tetrahydronaphthalene group in R1 position fit well into the binding pocket of the antagonist-bound conformation of TRPC6. Compound 1s showed an inhibitory potency order of TRPC3 (IC50 3.3 ± 0.13 μM) ≈ C6 (IC50 4.2 ± 0.1 μM) > C7 with good anti-gastric cancer activity in a micromolecular range against AGS and MKN-45, respectively. In addition, 1s inhibited the invasion and migration of MKN-45 cells in vitro.
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Affiliation(s)
- Yingjie Wei
- School
of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation
(Yantai University), Ministry of Education; Collaborative Innovation
Center of Advanced Drug Delivery System and Biotech Drugs in Universities
of Shandong, Yantai University, Yantai 264005, China
| | - Mengxian Zhang
- Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE)
and Hubei Province Engineering and Technology Research Center for
Fluorinated Pharmaceuticals, Wuhan University
School of Pharmaceutical Sciences, Wuhan 430071, China
| | - Zhenbin Lyu
- State
Key Laboratory of Virology, College of Science, Research Center for
Ecology, Laboratory of Extreme Environmental Biological Resources
and Adaptive Evolution, Innovation Center for Traditional Tibetan
Medicine Modernization and Quality Control, Tibet University, Lhasa 850000, China
| | - Guolin Yang
- State
Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory
for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu Province 211198, China
| | - Tian Tian
- State
Key Laboratory of Virology, College of Science, Research Center for
Ecology, Laboratory of Extreme Environmental Biological Resources
and Adaptive Evolution, Innovation Center for Traditional Tibetan
Medicine Modernization and Quality Control, Tibet University, Lhasa 850000, China
- Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE)
and Hubei Province Engineering and Technology Research Center for
Fluorinated Pharmaceuticals, Wuhan University
School of Pharmaceutical Sciences, Wuhan 430071, China
| | - Mingmin Ding
- Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE)
and Hubei Province Engineering and Technology Research Center for
Fluorinated Pharmaceuticals, Wuhan University
School of Pharmaceutical Sciences, Wuhan 430071, China
| | - Xiaodong Zeng
- Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE)
and Hubei Province Engineering and Technology Research Center for
Fluorinated Pharmaceuticals, Wuhan University
School of Pharmaceutical Sciences, Wuhan 430071, China
- Shenzhen
Institute of Wuhan University, Shenzhen 518057, China
| | - Fuchun Xu
- State
Key Laboratory of Virology, College of Science, Research Center for
Ecology, Laboratory of Extreme Environmental Biological Resources
and Adaptive Evolution, Innovation Center for Traditional Tibetan
Medicine Modernization and Quality Control, Tibet University, Lhasa 850000, China
| | - Pengyu Wang
- Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE)
and Hubei Province Engineering and Technology Research Center for
Fluorinated Pharmaceuticals, Wuhan University
School of Pharmaceutical Sciences, Wuhan 430071, China
| | - Fangfang Li
- School
of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation
(Yantai University), Ministry of Education; Collaborative Innovation
Center of Advanced Drug Delivery System and Biotech Drugs in Universities
of Shandong, Yantai University, Yantai 264005, China
| | - Yixuan Liu
- State
Key Laboratory of Virology, College of Science, Research Center for
Ecology, Laboratory of Extreme Environmental Biological Resources
and Adaptive Evolution, Innovation Center for Traditional Tibetan
Medicine Modernization and Quality Control, Tibet University, Lhasa 850000, China
| | - Zhengyu Cao
- State
Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory
for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu Province 211198, China
| | - Jing Lu
- School
of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation
(Yantai University), Ministry of Education; Collaborative Innovation
Center of Advanced Drug Delivery System and Biotech Drugs in Universities
of Shandong, Yantai University, Yantai 264005, China
- State
Key
Laboratory of Long-acting Targeting Drug Delivery Technologies, Luye Pharma Group Ltd., Yantai 264003, China
| | - Xuechuan Hong
- State
Key Laboratory of Virology, College of Science, Research Center for
Ecology, Laboratory of Extreme Environmental Biological Resources
and Adaptive Evolution, Innovation Center for Traditional Tibetan
Medicine Modernization and Quality Control, Tibet University, Lhasa 850000, China
- Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE)
and Hubei Province Engineering and Technology Research Center for
Fluorinated Pharmaceuticals, Wuhan University
School of Pharmaceutical Sciences, Wuhan 430071, China
- Shenzhen
Institute of Wuhan University, Shenzhen 518057, China
| | - Hongbo Wang
- School
of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation
(Yantai University), Ministry of Education; Collaborative Innovation
Center of Advanced Drug Delivery System and Biotech Drugs in Universities
of Shandong, Yantai University, Yantai 264005, China
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17
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Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors. Antibiotics (Basel) 2021; 10:antibiotics10020162. [PMID: 33562582 PMCID: PMC7915026 DOI: 10.3390/antibiotics10020162] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/25/2021] [Accepted: 02/02/2021] [Indexed: 12/18/2022] Open
Abstract
Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a-d, pyridine-2-one 3-10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17-23.87 µM, and of DHFR, with IC50 values of 4.33-5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.
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18
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Zhang H, Zhao S, Yu J, Yang W, Liu Z, Zhang L. Medicinal chemistry perspective of TRPM2 channel inhibitors: where we are and where we might be heading? Drug Discov Today 2020; 25:2326-2334. [PMID: 33065292 DOI: 10.1016/j.drudis.2020.09.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/26/2020] [Accepted: 09/30/2020] [Indexed: 01/06/2023]
Abstract
Transient receptor potential melastatin 2 (TRPM2) is a Ca2+- permeable nonselective cation channel that is involved in diverse biological functions as a cellular sensor for oxidative stress and temperature. It has been considered a promising therapeutic target for the treatment of ischemia/reperfusion (IR) injury, inflammation, cancer, and neurodegenerative diseases. Development of highly potent and selective TRPM2 inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we describe the molecular structures and gating mechanism of the TRPM2 channel, and offer a comprehensive review of advances in the discovery of TRPM2 inhibitors. Furthermore, we analyze the properties of reported TRPM2 inhibitors with an emphasis on how specific inhibitors targeting this channel could be better developed.
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Affiliation(s)
- Han Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Siqi Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Jie Yu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Wei Yang
- Department of Biophysics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
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19
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Lee B, Willis AC, Ward JS, Smith WT, Lan P, Banwell MG. Iterative Suzuki-Miyaura Cross-coupling/Bromo-desilylation Reaction Sequences for the Assembly of Chemically Well-defined, Acyclic Oligopyrrole/Benzenoid Hybrids Embodying Mixed Modes of Connectivity. Chem Asian J 2020; 15:3059-3081. [PMID: 32749069 DOI: 10.1002/asia.202000740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/30/2020] [Indexed: 11/12/2022]
Abstract
Syntheses of a range of chemically well-defined oligopyrrole/benzenoid hybrids are described using tandem Suzuki-Miyaura cross-coupling/bromo-desilyation reaction sequences for linking borylated pyrroles, halogenated pyrroles and/or dibromobenzenes to one another. By such means, including iterative variants, a range of all α-linked, all β-linked oligopyrroles as well as certain combinations thereof have been assembled, some of them for the first time. The conductivities of iodine-treated thin films formed from certain such systems have been determined.
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Affiliation(s)
- BoRa Lee
- Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
| | - Anthony C Willis
- Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
| | - Jas S Ward
- Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
| | | | - Ping Lan
- Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632/, Zhuhai, 519070, Guangdong, China
| | - Martin G Banwell
- Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia.,Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632/, Zhuhai, 519070, Guangdong, China
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20
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Fernández-Ballester G, Fernández-Carvajal A, Ferrer-Montiel A. Targeting thermoTRP ion channels: in silico preclinical approaches and opportunities. Expert Opin Ther Targets 2020; 24:1079-1097. [PMID: 32972264 DOI: 10.1080/14728222.2020.1820987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION A myriad of cellular pathophysiological responses are mediated by polymodal ion channels that respond to chemical and physical stimuli such as thermoTRP channels. Intriguingly, these channels are pivotal therapeutic targets with limited clinical pharmacology. In silico methods offer an unprecedented opportunity for discovering new lead compounds targeting thermoTRP channels with improved pharmacological activity and therapeutic index. AREAS COVERED This article reviews the progress on thermoTRP channel pharmacology because of (i) advances in solving their atomic structure using cryo-electron microscopy and, (ii) progress on computational techniques including homology modeling, molecular docking, virtual screening, molecular dynamics, ADME/Tox and artificial intelligence. Together, they have increased the number of lead compounds with clinical potential to treat a variety of pathologies. We used original and review articles from Pubmed (1997-2020), as well as the clinicaltrials.gov database, containing the terms thermoTRP, artificial intelligence, docking, and molecular dynamics. EXPERT OPINION The atomic structure of thermoTRP channels along with computational methods constitute a realistic first line strategy for designing drug candidates with improved pharmacology and clinical translation. In silico approaches can also help predict potential side-effects that can limit clinical development of drug candidates. Together, they should provide drug candidates with upgraded therapeutic properties.
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Affiliation(s)
- Gregorio Fernández-Ballester
- Professor Gregorio Fernández-Ballester. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández , Alicante, Spain
| | - Asia Fernández-Carvajal
- Professor Gregorio Fernández-Ballester. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández , Alicante, Spain
| | - Antonio Ferrer-Montiel
- Professor Gregorio Fernández-Ballester. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández , Alicante, Spain
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21
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Zhang H, He X, Wang X, Yu B, Zhao S, Jiao P, Jin H, Liu Z, Wang K, Zhang L, Zhang L. Design, synthesis and biological activities of piperidine-spirooxadiazole derivatives as α7 nicotinic receptor antagonists. Eur J Med Chem 2020; 207:112774. [PMID: 32882607 DOI: 10.1016/j.ejmech.2020.112774] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 02/02/2023]
Abstract
α: 7 nicotinic acetylcholine receptors (nAChRs) expressed in the nervous and immune systems have been suggested to play important roles in the control of inflammation. However, the lack of antagonist tools specifically inhibiting α7 nAChR impedes the validation of the channel as therapeutic target. To discover a selective α7 antagonist, we started a pharmacophore-based virtual screening and identified a piperidine-spirooxadiazole derivative T761-0184 that acts as a α7 antagonist. A series of novel piperidine-spirooxadiazole derivatives were subsequently synthesized and evaluated using two-electrode voltage clamp (TEVC) assay in Xenopus oocytes. Lead compounds from two series inhibited α7 with their IC50 values ranging from 3.3 μM to 13.7 μM. Compound B10 exhibited α7 selectivity over other α4β2 and α3β4 nAChR subtypes. The analysis of structure-activity relationship (SAR) provides valuable insights for further development of selective α7 nAChR antagonists.
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Affiliation(s)
- Han Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Xiaomeng He
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Xintong Wang
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Bo Yu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Siqi Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Peili Jiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Hongwei Jin
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - KeWei Wang
- Department of Pharmacology, Qingdao University School of Phamacy, Qingdao, 266021, PR China.
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Lihe Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
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22
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Wang M, Li J, Dong S, Cai X, Simaiti A, Yang X, Zhu X, Luo J, Jiang LH, Du B, Yu P, Yang W. Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction. Part Fibre Toxicol 2020; 17:23. [PMID: 32513195 PMCID: PMC7281956 DOI: 10.1186/s12989-020-00353-3] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 05/26/2020] [Indexed: 01/26/2023] Open
Abstract
Background Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of above-mentioned mechanisms in NPs-induced pulmonary inflammation are still largely obscure. Considered that NPs exposure in modern society is often unavoidable, it is highly desirable to develop effective strategies that could help to prevent nanomaterials-induced pulmonary inflammation. Results Pulmonary inflammation induced by intratracheal instillation of silica nanoparticles (SiNPs) in C57BL/6 mice was prevented by PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor. In human lung bronchial epithelial (BEAS-2B) cells, exposure to SiNPs reduced cell viability, and induced ROS generation, impairment in lysosome function and autophagic flux. Inhibition of ROS generation, PARP and TRPM2 channel suppressed SiNPs-induced lysosome impairment and autophagy dysfunction and consequent inflammatory responses. Consistently, SiNPs-induced pulmonary inflammation was prevented in TRPM2 deficient mice. Conclusion The ROS/PARP/TRPM2 signaling is critical in SiNPs-induced pulmonary inflammation, providing novel mechanistic insights into NPs-induced lung injury. Our study identifies TRPM2 channel as a new target for the development of preventive and therapeutic strategies to mitigate nanomaterials-induced lung inflammation. Graphical abstract ![]()
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Affiliation(s)
- Mingxiang Wang
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Jin Li
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Shunni Dong
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science & Engineering, Zhejiang University, Hangzhou, China
| | - Xiaobo Cai
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.,Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Aili Simaiti
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Xin Yang
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Xinqiang Zhu
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.,The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, P. R. China
| | - Jianhong Luo
- Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Lin-Hua Jiang
- Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, P. R. China.,School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
| | - Binyang Du
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science & Engineering, Zhejiang University, Hangzhou, China.
| | - Peilin Yu
- Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
| | - Wei Yang
- Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
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23
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Mou J, Chen N, Zhao Y, Qi H, Meng S, Xiang R, Pei D. An Aqueous Facile Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives by Reverse Zinc Oxide Micelles as Nanoreactor. Front Chem 2020; 8:239. [PMID: 32391312 PMCID: PMC7193868 DOI: 10.3389/fchem.2020.00239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 03/12/2020] [Indexed: 12/02/2022] Open
Abstract
A green synthetic protocol has been developed for the efficient preparation of 2,3-dihydroquinazolin−4(1H)-one derivatives with excellent yield in aqueous media. Reverse zinc oxide micelles catalyzed the reactions efficiently and selectively as the hallow nanoreactor. Moreover, the catalyst was reusable without significant loss of catalytic efficiency. The notable advantages of the procedure are high yields and mild reaction conditions, simple operation, nonchromatographic purification, environmentally friendly and good versatile substrates.
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Affiliation(s)
- Jie Mou
- Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.,School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Ninghai Chen
- School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yu Zhao
- Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Hao Qi
- School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Sihan Meng
- School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Rui Xiang
- Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Dongsheng Pei
- Department of Pathology, Xuzhou Medical University, Xuzhou, China
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24
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Islam MS. Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells. Cells 2020; 9:cells9030685. [PMID: 32168890 PMCID: PMC7140661 DOI: 10.3390/cells9030685] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 03/06/2020] [Accepted: 03/08/2020] [Indexed: 12/17/2022] Open
Abstract
Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines.
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Affiliation(s)
- Md. Shahidul Islam
- Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Research Center, 5th floor, SE-118 83 Stockholm, Sweden;
- Department of Emergency Care and Internal Medicine, Uppsala University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden
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25
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Cruz-Torres I, Backos DS, Herson PS. Characterization and Optimization of the Novel Transient Receptor Potential Melastatin 2 Antagonist tatM2NX. Mol Pharmacol 2020; 97:102-111. [PMID: 31772034 PMCID: PMC6964147 DOI: 10.1124/mol.119.117549] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable channel activated by adenosine diphosphate ribose metabolites and oxidative stress. TRPM2 contributes to neuronal injury in the brain caused by stroke and cardiac arrest among other diseases including pain, inflammation, and cancer. However, the lack of specific inhibitors hinders the study of TRPM2 in brain pathophysiology. Here, we present the design of a novel TRPM2 antagonist, tatM2NX, which prevents ligand binding and TRPM2 activation. We used mutagenesis of tatM2NX to determine the structure-activity relationship and antagonistic mechanism on TRPM2 using whole-cell patch clamp and Calcium imaging in human embryonic kidney 293 cells with stable human TRPM2 expression. We show that tatM2NX inhibits over 90% of TRPM2 channel currents at concentrations as low as 2 μM. Moreover, tatM2NX is a potent antagonist with an IC50 of 396 nM. Our results from tatM2NX mutagenesis indicate that specific residues within the tatM2NX C terminus are required to confer antagonism on TRPM2. Therefore, the peptide tatM2NX represents a new tool for the study of TRPM2 function in cell biology and enhances our understanding of TRPM2 in disease. SIGNIFICANCE STATEMENT: TatM2NX is a potent TRPM2 channel antagonist with the potential for clinical benefit in neurological diseases. This study characterizes interactions of tatM2NX with TRPM2 and the mechanism of action using structure-activity analysis.
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Affiliation(s)
- I Cruz-Torres
- Departments of Pharmacology (I.C.-T., P.S.H.) and Anesthesiology (P.S.H.) and Neuronal Injury & Plasticity Program (I.C.-T., P.S.H.), University of Colorado School of Medicine, Aurora, Colorado; and Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado (D.S.B.)
| | - D S Backos
- Departments of Pharmacology (I.C.-T., P.S.H.) and Anesthesiology (P.S.H.) and Neuronal Injury & Plasticity Program (I.C.-T., P.S.H.), University of Colorado School of Medicine, Aurora, Colorado; and Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado (D.S.B.)
| | - P S Herson
- Departments of Pharmacology (I.C.-T., P.S.H.) and Anesthesiology (P.S.H.) and Neuronal Injury & Plasticity Program (I.C.-T., P.S.H.), University of Colorado School of Medicine, Aurora, Colorado; and Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado (D.S.B.)
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26
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Reddy MM, Sivaramakrishna A. Remarkably flexible quinazolinones—synthesis and biological applications. J Heterocycl Chem 2019. [DOI: 10.1002/jhet.3844] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Manne Madhava Reddy
- Department of Chemistry, School of Advanced SciencesVellore Institute of Technology (VIT) Vellore Tamil Nadu India
| | - Akella Sivaramakrishna
- Department of Chemistry, School of Advanced SciencesVellore Institute of Technology (VIT) Vellore Tamil Nadu India
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27
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Green Synthesis of Substituted Anilines and Quinazolines from Isatoic Anhydride-8-amide. Sci Rep 2019; 9:14258. [PMID: 31582788 PMCID: PMC6776664 DOI: 10.1038/s41598-019-50776-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 09/18/2019] [Indexed: 12/17/2022] Open
Abstract
Synthetic methods used to generate substituted anilines and quinazolines, both privileged pharmacological structures, are cumbersome, hazardous or, in some cases, unavailable. We developed a straightforward method for making isatoic anhydride-8-amide from isatin-7-carboxylic acid as a tool to easily produce a range of quinazoline and substituted aniline derivatives using adaptable pH-sensitive cyclization chemistry. The approaches are inexpensive, simple, fast, efficient at room temperature and scalable, enabling the synthesis of both established and new quinazolines and also highly substituted anilines including cyano derivatives.
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28
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Fourgeaud L, Dvorak C, Faouzi M, Starkus J, Sahdeo S, Wang Q, Lord B, Coate H, Taylor N, He Y, Qin N, Wickenden A, Carruthers N, Lovenberg TW, Penner R, Bhattacharya A. Pharmacology of JNJ-28583113: A novel TRPM2 antagonist. Eur J Pharmacol 2019; 853:299-307. [PMID: 30965058 DOI: 10.1016/j.ejphar.2019.03.043] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 03/13/2019] [Accepted: 03/22/2019] [Indexed: 12/11/2022]
Abstract
Transient receptor potential melastatin type 2 (TRPM2) is a cation channel activated by free intracellular ADP-ribose and reactive oxygen species. TRPM2 signaling has been linked to the pathophysiology of CNS disorders such as neuropathic pain, bipolar disorder and Alzheimer's disease. In this manuscript, we describe the discovery of JNJ-28583113, a potent brain penetrant TRPM2 antagonist. Ca2+ flux assays in cells overexpressing TRPM2 and electrophysiological recordings were used to test the pharmacology of JNJ-28583113. JNJ-28583113 was assayed in vitro on GSK-3 phosphorylation levels, cell death, cytokine release in microglia and unbiased morphological phenotypic analysis. Finally, we dosed animals to evaluate its pharmacokinetic properties. Our results showed that JNJ-28583113 is a potent (126 ± 0.5 nM) TRPM2 antagonist. Blocking TRPM2 caused phosphorylation of GSK3α and β subunits. JNJ-28583113 also protected cells from oxidative stress induced cell death as well as morphological changes induced by non-cytotoxic concentrations of H2O2. In addition, inhibiting TRPM2 blunted cytokine release in response to pro-inflammatory stimuli in microglia. Lastly, we showed that JNJ-28583113 was brain penetrant but not suitable for systemic dosing as it was rapidly metabolized in vivo. While the in-vitro pharmacology of JNJ-28583113 is the best in class, its in-vivo properties would need optimization to assist in further probing key roles of TRPM2 in CNS pathophysiology.
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Affiliation(s)
- Lawrence Fourgeaud
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA.
| | - Curt Dvorak
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Malika Faouzi
- Centre for Biomedical Research at the Queen's Medical Centre, Honolulu, HI, 96813, USA
| | - John Starkus
- Centre for Biomedical Research at the Queen's Medical Centre, Honolulu, HI, 96813, USA
| | - Sunil Sahdeo
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Qi Wang
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Brian Lord
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Heather Coate
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Natalie Taylor
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Yingbo He
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Ning Qin
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Alan Wickenden
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Nicholas Carruthers
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Timothy W Lovenberg
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Reinhold Penner
- Centre for Biomedical Research at the Queen's Medical Centre, Honolulu, HI, 96813, USA
| | - Anindya Bhattacharya
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA
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29
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Zhang X, Li Z, Ding Q, Li X, Fan X, Zhang G. Alkylamino-Directed One-Pot Reaction of N
-Alkyl Anilines with CO, Amines and Aldehydes Leading to 2,3-Dihydroquinazolin-4(1H
)-ones. Adv Synth Catal 2019. [DOI: 10.1002/adsc.201801267] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Xiaopeng Zhang
- Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering; Henan Normal University; Xinxiang 453007 People's Republic of China
| | - Zhengwei Li
- Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering; Henan Normal University; Xinxiang 453007 People's Republic of China
| | - Qianqian Ding
- Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering; Henan Normal University; Xinxiang 453007 People's Republic of China
| | - Xiaochuan Li
- Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering; Henan Normal University; Xinxiang 453007 People's Republic of China
| | - Xuesen Fan
- Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering; Henan Normal University; Xinxiang 453007 People's Republic of China
| | - Guisheng Zhang
- Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering; Henan Normal University; Xinxiang 453007 People's Republic of China
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