Design, synthesis and molecular modeling study of certain 4-Methylbenzenesulfonamides with CDK2 inhibitory activity as anticancer and radio-sensitizing agents
| Autor: | Helmy I. Heiba, Mostafa M. Ghorab, Fatma A. Ragab, Mohamed S. A. Elsayed, Walid M. Ghorab |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Molecular model Antineoplastic Agents Biochemistry 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Catalytic Domain Cell Line Tumor Drug Discovery Structure–activity relationship Humans Molecular Biology IC50 Protein Kinase Inhibitors Cell Proliferation chemistry.chemical_classification Sulfonamides Binding Sites biology Cell growth Organic Chemistry Cyclin-Dependent Kinase 2 Active site Molecular Docking Simulation 030104 developmental biology Cell killing Enzyme chemistry Docking (molecular) Gamma Rays 030220 oncology & carcinogenesis Drug Design biology.protein Drug Screening Assays Antitumor Toluene |
| Zdroj: | Bioorganic chemistry. 80 |
| ISSN: | 1090-2120 |
| Popis: | Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC50 values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC50 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC50 of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC50 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect