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Design, synthesis and SAR of novel 7-azaindole derivatives as potential Erk5 kinase inhibitor with anticancer activity. 2023

Qin Zhang, and Xintao Gao, and Xiyu Duan, and Han Liang, and Mingyuan Gao, and Dianquan Dong, and Chuanlong Guo, and Longjiang Huang
State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, 266042 Qingdao, Shandong, China.

The extracellular signal-regulated kinase 5 (Erk5) signaling plays a crucial role in cancer, and regulating its activity may have potential in cancer chemotherapy. In this study, a series of novel 7-azaindole derivatives (4a-5o) were designed and synthesized. Their antitumor activities on human lung cancer A549 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 4',6-diamidino-2-phenylindole (DAPI) staining and colony formation assay. Among them, compounds 4a, 4 h, 5d and 5j exhibited good anti-proliferative activity with the IC50 values of 6.23 µg/mL, 8.52 µg/mL, 7.33 µg/mL and 4.56 µg/mL, respectively, equivalent to Erk5 positive control XMD8-92 (IC50 = 5.36 µg/mL). The results of structure-activity relationships (SAR) showed that double bond on the piperidine ring and N atoms at the N7 position of 7-azaindole was essential for their antiproliferative activity. Furthermore, compounds 4a and 5j exhibited good inhibition on Erk5 kinase through Western blot analysis and possible action site of compounds with Erk5 kinase was elucidated by molecular docking.

UI MeSH Term Description Entries
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D048054 Mitogen-Activated Protein Kinase 7 A 110-kDa extracellular signal-regulated MAP kinase that is activated in response to cellular stress and by GROWTH FACTOR RECEPTORS-mediated pathways. Extracellular Signal-Regulated Kinase 5,BMK1 Kinase,Big MAP Kinase 1,ERK5 Kinase,MAPK7 Mitogen-Activated Protein Kinase,Mitogen-Activated Protein Kinase 7 Isoform 1,Mitogen-Activated Protein Kinase 7 Isoform 2,Extracellular Signal Regulated Kinase 5,Kinase, BMK1,Kinase, ERK5,MAPK7 Mitogen Activated Protein Kinase,Mitogen Activated Protein Kinase 7,Mitogen Activated Protein Kinase 7 Isoform 1,Mitogen Activated Protein Kinase 7 Isoform 2
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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