Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability

• Published in: Bioorganic chemistry 2018-02, Vol.76, p.420-436
• Main Authors: Narasimha Rao, M.P., Nagaraju, Burri, Kovvuri, Jeshma, Polepalli, Sowjanya, Alavala, Sateesh, Vishnuvardhan, M.V.P.S., Swapna, P., Nimbarte, Vijaykumar D., Lakshmi, Jerripothula K., Jain, Nishant, Kamal, Ahmed
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Binding Sites; Caspase 3 - metabolism; Cell cycle; Cell Line, Tumor; Cytotoxicity; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints - drug effects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; Imidazothiadiazoles; Molecular Docking Simulation; Molecular Structure; Oxindoles - chemical synthesis; Oxindoles - chemistry; Oxindoles - metabolism; Oxindoles - pharmacology; Protein Binding; Structure-Activity Relationship; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - metabolism; Thiadiazoles - pharmacology; Tubulin - chemistry; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - metabolism; Tubulin Modulators - pharmacology; Tubulin polymerization
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.11.021

[Display omitted] •Imidazo[2,1-b][1,3,4]thiadiazole linked indolin-2-one conjugates were synthesized.•Moderate to significant cytotoxicity with GI50 values from 0.13 to 3.8 μΜ.•Conjugates 7, 14 and 15 exhibited, inhibition of tubulin assembly.•In addition they exhibited apoptosis in HeLa cell line.•These conjugates bind in the colchicine-binding site of the tubulin. A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8 μΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with αAsn101, αThr179, αSer178, βCys241, βLys254 and βLys352 in the colchicine-binding site of the tubulin.