BIOMAT Database Logo BIOMAT Database Logo

Design, synthesis and biological evaluation of coumarin derivatives as potential BRD4 inhibitors. 2022

Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.

UI MeSH Term Description Entries
D009687 Nuclear Proteins Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. Nucleolar Protein,Nucleolar Proteins,Nuclear Protein,Protein, Nuclear,Protein, Nucleolar,Proteins, Nuclear,Proteins, Nucleolar
D003374 Coumarins Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid. 1,2-Benzopyrone Derivatives,1,2-Benzopyrones,Coumarin Derivative,Coumarine,1,2-Benzo-Pyrones,Benzopyran-2-ones,Coumarin Derivatives,Coumarines,1,2 Benzo Pyrones,1,2 Benzopyrone Derivatives,1,2 Benzopyrones,Benzopyran 2 ones,Derivative, Coumarin,Derivatives, 1,2-Benzopyrone,Derivatives, Coumarin
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
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
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
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

Related Publications

Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors.
October 2016, Bioorganic chemistry,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of imidazolopyridone derivatives as novel BRD4 inhibitors.
January 2021, Bioorganic & medicinal chemistry,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.
January 2023, Bioorganic & medicinal chemistry,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors.
October 2019, Bioorganic & medicinal chemistry letters,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors.
December 2020, European journal of medicinal chemistry,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, Synthesis, and in vitro Biological Evaluation of 3,5-Dimethylisoxazole Derivatives as BRD4 Inhibitors.
July 2018, ChemMedChem,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis, biological evaluation, and molecular modeling of coumarin-piperazine derivatives as acetylcholinesterase inhibitors.
November 2013, Archiv der Pharmazie,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of novel coumarin thiazole derivatives as α-glucosidase inhibitors.
April 2016, Bioorganic chemistry,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents.
March 2019, Bioorganic chemistry,
Qi-Hang Cui, and Wen-Bo Li, and Zhao-Yang Wang, and Kai-Yan Xu, and Shuai Wang, and Jian-Tao Shi, and Li-Wen Zhang, and Shi-Wu Chen
Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4 inhibitors.
July 2019, Bioorganic & medicinal chemistry,
Copied contents to your clipboard!