Design, synthesis and biological evaluation of 4-(4-aminophenoxy)picolinamide derivatives as potential antitumor agents. 2023

Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China; Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.

Cancer is a leading cause of death in humans. Molecular targeted therapy for cancer has become a research hotspot as it is associated with low toxicity and high efficiency. In this study, a total of 36 derivatives of 4-(4-aminophenoxy)pyridinamide were designed and synthesized, based on the analysis of the binding patterns of cabozantinib and BMS-777607 to MET protein. Most target compounds exhibited moderate to excellent antiproliferative activity against three different cell lines (A549, HeLa and MCF-7). A total of 7 compounds had stronger inhibitory activities than cabozantinib, and the IC50 value of the most promising compound 46 was 0.26 μM against the A549 cells, which was 2.4 times more active than that of cabozantinib. The structure-activity relationship of the target compounds was analyzed and summarized, and the action mechanism was discussed. The acridine orange (AO) staining assay and cell cycle apoptosis revealed that compound 46 dose-dependently induced apoptosis of A549 cells, and blocked the cells mainly in G0/G1 phase. The IC50 value of compound 46 on c-Met kinase was 46.5 nM. Further docking studies and molecular dynamics simulations signaled that compound 46 formed four key hydrogen bonds to c-Met kinase, and these key amino acids played a major role in binding free energy. In addition, compound 46 also showed good pharmacokinetic characteristics in rats. In conclusion, compound 46 is a promising antitumor agent.

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
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
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
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
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
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
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

Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
May 2012, Molecules (Basel, Switzerland),
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
May 2019, Archiv der Pharmazie,
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
November 2021, Drug development research,
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
December 2022, Journal of enzyme inhibition and medicinal chemistry,
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
September 2019, European journal of medicinal chemistry,
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
May 2024, Bioorganic chemistry,
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
September 2018, Molecules (Basel, Switzerland),
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
January 2019, Frontiers in chemistry,
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
July 2014, Molecules (Basel, Switzerland),
Jintian Dai, and Jianqing Zhang, and Dongxue Fu, and Meng Liu, and Han Zhang, and Sheng Tang, and Linxiao Wang, and Shan Xu, and Wufu Zhu, and Qidong Tang, and Pengwu Zheng, and Ting Chen
April 2019, MedChemComm,
Copied contents to your clipboard!