Synthesis and Biological Evaluation of Imidazo[2,1-b][1,3,4]thiadiazole-Linked Oxindoles as Potent Tubulin Polymerization Inhibitors
| Autor: | M. P. Narasimha Rao, Nishant Jain, P. Swapna, Ahmed Kamal, Kishore Mullagiri, Jeshma Kovvuri, Sowjanya Polepalli, Vijaykumar D. Nimbarte, Pompi Das |
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| Rok vydání: | 2014 |
| Předmět: |
Indoles
Stereochemistry Antineoplastic Agents Biochemistry Tubulin Polymerization Inhibitors chemistry.chemical_compound Tubulin Cell Line Tumor Thiadiazoles Drug Discovery Humans General Pharmacology Toxicology and Pharmaceutics Methylene Cytotoxicity IC50 Pharmacology Combretastatin Binding Sites biology Organic Chemistry Imidazoles Tubulin Modulators Oxindoles Protein Structure Tertiary G2 Phase Cell Cycle Checkpoints Molecular Docking Simulation chemistry Cell culture Docking (molecular) biology.protein M Phase Cell Cycle Checkpoints Molecular Medicine Drug Screening Assays Antitumor Colchicine |
| Zdroj: | ChemMedChem. 9:1463-1475 |
| ISSN: | 1860-7179 |
| Popis: | A series of imidazo[2,1-b][1,3,4]thiadiazole-linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti-proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)-5-fluoro-3-((6-p-tolyl-2-(3,4,5-trimethoxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one), 11 ((E)-3-((6-p-tolyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one), and 15 ((E)-6-chloro-3-((6-phenyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one) exhibited potent anti-proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G2 /M phase, inhibition of tubulin assembly, and increased cyclin-B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC50 range of 1.1-1.6 μM, and inhibited tubulin polymerization with an IC50 value (0.15 μM) lower than that of combretastatin A-4 (1.16 μM). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin. |
| Databáze: | OpenAIRE |
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